Research Models

ALS Mouse Models

Dozens of rodents have been generated that model various aspects of ALS, like motor impairment or degeneration of motor neurons. No model recapitulates the human disease perfectly. By organizing information related to the phenotypic characterization of selected ALS models, this resource conveys what is known about each one and facilitates comparison between models. The curation of ALS models was supported in part by a grant from the NINDS.

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44 Models

Name Other Names Strain Name Genetic Background Gene Mutation Modification Info Modification Disease Neuropathology Behavior/Cognition Other Phenotype Availability Primary Paper Visualization
Mouse Models (44)
GFP-(GA)50 C57BL/6J An adeno-associated viral (AAV) vector encoding 50 glycine-alanine (GA) repeats tagged with green fluorescent protein was injected into the ventricles of neonatal mice. Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Poly(GA)- and ubiquitin-positive inclusions in neurons are primarily cytoplasmic and also co-localize with HR23A and HR23B proteins and the nuclear pore complex proteins RanGAP1 and Pom121. Neuron loss and astrogliosis in cortex and hippocampus. Motor deficits, impaired coordination, hyperactivity, increased anxiety, and deficits in contextual and cued fear conditioning. Viral construct available through Leonard Petrucelli. Zhang et al., 2016 Yes
GFP–(GR)100 C57BL/6J An adeno-associated viral (AAV) vector encoding 100 glycine-arginine (GR) repeats tagged with green fluorescent protein was injected into the ventricles of neonatal mice. Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Progressive neuron loss in cortex and hippocampus, gliosis. Lacks poly(GR) inclusions. Rare TDP-43 inclusions. Progressive motor deficits and age-dependent cognitive impairment. Viral construct available through Leonard Petrucelli. Zhang et al., 2018 Yes
Brown, C9-BAC[GGGGCC]500 SJL/B6 C9orf72 Hexanucleotide repeat in C9ORF72 This transgenic mouse carries a bacterial artificial chromosome (BAC) containing exons 1 through 6 of human C9orf72 with ~500 GGGGCC repeat motifs and ~140.5 kb upstream. C9orf72: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Widespread RNA foci throughout the nervous system starting at 3 months of age, especially comprised of sense transcript. Dipeptide repeats (e.g., poly-GP) as soluble protein and insoluble aggregates. No neurodegeneration. No TDP-43 aggregation, gliosis, inflammation, or synapse loss. No overt behavioral abnormalities compared to non-Tg controls. Assessment included grip strength, Rotarod performance, and intruder test. Viable, fertile, born in Mendelian ratios. Available through Robert Brown Peters et al., 2015 Yes
Baloh/Lutz, C9-BAC[GGGGCC]100-1000, Tg(C9orf72_3) line 112, Line F112 C57BL/6J-Tg(C9orf72_i3)112Lutzy/J C57BL/6J C9orf72 Hexanucleotide repeat in C9ORF72 This transgenic mouse carries a bacterial artificial chromosome (BAC) containing full-length human C9ORF72 sequence with ~100-1000 repeats. C9orf72: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Widespread RNA foci throughout the nervous system first assessed at 3 months of age. Soluble dipeptide repeats (e.g., poly-GP) and insoluble aggregates. No neurodegeneration. No TDP-43 aggregation, gliosis, inflammation, or obvious synapse loss. No behavioral abnormalities compared to non-Tg controls at either young age (3 months) or advanced age (18 months). Tests included: grip strength, Rotarod performance, open-field, three-chamber, and Y-maze. Viable, fertile, born in Mendelian ratios. The Jackson Lab: Stock# 023099; Live O'Rourke et al., 2015 Yes
(G4C2)149, 149-repeat mice C57BL/6J C9orf72 Hexanucleotide repeat in C9ORF72 An adeno-associated viral (AAV) vector was used to deliver 149 repeats of the hexanucleotide GGGGCC motif, along with the 5' (119 bp) and 3' (100 bp) flanking regions of the C9ORF72 gene, driven by the β-actin promoter. Virus was injected into the lateral ventricles of wild-type pups on postnatal day 0. C9orf72: Virus Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Intranuclear foci containing antisense and antisense repeat RNA; cytoplasmic inclusions containing sense and antisense dipeptide repeat proteins; accumulation of phosphorylated TDP-43 and stress granule-associated proteins; neuron loss and gliosis. Motor and cognitive deficits emerge between 3 and 6 months of age. Hyperactivity seen by 3 months. Mislocalization of RanGAP1 suggests nucleocytoplasmic transport defects. Unknown. Chew et al., 2019 Yes
66-repeat mice, Petrucelli’s AAV C9 model C57BL/6 C9orf72 Hexanucleotide repeat in C9ORF72 An adeno-associated viral (AAV) vector was used to deliver a sequence of 66 repeats of the hexanucleotide, GGGGCC. The virus was injected into the cerebral ventricles of P0 pups. C9orf72: Virus Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Nuclear RNA foci in neurons, dipeptide aggregates (GA, GP, and GR), cytoplasmic inclusions of phosphorylated TDP-43, neuronal loss, brain atrophy, and gliosis. Subtle behavioral deficits including anxiety-like behavior, hyperactivity, and antisocial behavior. Subtle motor impairment and failure to improve on the Rotarod. Reduced body weight in females by 6 months. Viral construct available through Leonard Petrucelli Chew et al., 2015 Yes
C9orf72 KO, 3110043O21Rik Knock-out 3110043O21Riktm1(KOMP)Mbp C57BL/6N C9orf72 The mouse 3110043O21Rik gene (homologue of human C9orf72) was inactivated by deleting a region containing exons 2-6, which includes the start codon. The targeting vector contained expression cassettes, flanked by FRT sites, for lacZ and neo as selectable markers. C9orf72: Knock-Out Frontotemporal Dementia, Amyotrophic Lateral Sclerosis Chromatolytic structures are observed with H&E staining, in gray and white matter of the spinal cord. Neurodegeneration not present. Normal sensorimotor coordination and limb strength. Reduced activity in open-field test. Spleens and lymph nodes enlarged by 1 month, size increases with age. Histology shows enlarged debris-filled cells. Available through the UC Davis Knockout Mouse Project (KOMP) Repository, gene 3110043021Rik; Cryopreserved O'Rourke et al., 2016 Yes
CamKII-tTA;(GR)80 (line 16), CamKII;(GR)80 C57BL/6 CamKII-tTA;(GR)80 mice are produced by crossing a responder line carrying a (GGXCGX)80 sequence downstream of a tetracycline operon–responsive element (TRE) to an activator line expressing a tetracycline-controlled transactivator (tTA) under control of the CaMKIIα promoter. Bi-transgenic progeny constitutively express poly(GR) until transgene expression is suppressed by administration of the tetracycline analog doxycycline (DOX). Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Neuron loss in the frontal cortex, beginning between 3 and 6 months of age. Microgliosis and astrogliosis evident at 6 and 9 months, respectively. No TDP-43 inclusions seen in mice studied up to 8 months of age. DNA damage and mitochondrial abnormalities observed. Deficits in social behavior and increased anxiety emerge between 3 and 6 months. Working memory is intact at least through 9 months of age. Morphological defects in mitochondria seen in mice as young as 3 months of age. Disease-related phenotypes were prevented or reversed by reducing levels of poly(GR) in adult mice. Unknown. Choi et al., 2019 Yes
B6(C3H)-Sod1m1H/J C57BL/6J SOD1 D83G in SOD1 This mouse has a point mutation (A>G) in the endogenous murine Sod1 gene, resulting from exposure to the chemical mutagen N-ethyl-N-nitrosourea (ENU). The endogenous murine Sod1 promoter drives expression of the mutant protein, which carries a D83G missense mutation. SOD1: Other Amyotrophic Lateral Sclerosis Upper and lower motor neuron loss in specific regions (layer V of motor cortex and lumbar spinal cord). Gliosis in spinal cord. Denervation of hindlimb muscle. Progressive motor impairments, including tremor, gait abnormalities, decreased grip strength, and impaired Rotarod performance. Liver tumors, kyphosis (hunched back), reduced body weight, loss of SOD1 activity. The Jackson Lab: Stock# 020440; Cryopreserved Joyce et al., 2015 Yes
FUSd14 B6C3F1 FUS FUS Δ14 Recombinant adeno-associated virus (AAV) to express mutant human FUS in the brain. Viral injection into the ventricles of P0 pups. Human FUS driven by the cytomegalovirus enhancer/chicken β-actin promoter. cDNA encodes C-terminal truncation, which lacks exon 14, and thus the entire nuclear localization signal. FUS: Virus Frontotemporal Dementia, Amyotrophic Lateral Sclerosis Widespread neuronal cytoplasmic inclusions (NCIs) by 3 months of age. Inclusions were FUS-positive and often co-labeled with ubiquitin.  No overt neurodegeneration or reactive gliosis. No overt motor phenotypes at 3 months of age. Viral construct available through Thomas Kukar Verbeeck et al., 2012 Yes
B6N;B6J-Fustm1Emcf/H C57BL6/J FUS FUSDelta14 truncation mutation The Fus gene in C57BL6/N mouse embryonic stem cells (ESC) was modified through homologous recombination using a targeting vector designed to introduce the following changes: g.13845 A>G (mutation at splice acceptor site of intron 13); g.14230 C>T, g.14232 A>T, g.14234C>G, g.14260 A>G, and g.14266 ATTA insertion, to humanize the coding sequence of exon 15. FUS: Knock-In Amyotrophic Lateral Sclerosis Progressive (not developmental) loss of lumbar spinal motor neurons, starting by 12 months of age; partial denervation of hindlimb muscles. Mislocalization of mutant FUS from nucleus to cytoplasm. Hindlimb motor impairment by 15 months. Premature death, beginning at 19 months of age. European Mouse Mutant Archive (EM:11106) Devoy et al., 2017 Yes
Fus-dNLS, Fus-deltaNLS, Fus-ΔNLS/+ C57Bl/6 Fus FUS ΔNLS A targeting vector encoding exons 13 and 14 of FUS followed by three stop codons and a poly A signal was inserted between exons 12 and 13 of FUS. These elements are flanked by a pair of loxP sites. Insertion of this transgene results in the exclusion of exon 15 and the NLS unless Cre-recombinase is expressed to excise the transgene. Fus: Knock-In Amyotrophic Lateral Sclerosis The spinal cord exhibited FusΔNLS mislocalization, a loss of motor neurons, and ubiquitin pathology. No impairments in grip strength or rotarod performance. Irregular walking patterns and reduced hang time on inverted grid test were observed. Altered electrical activity of the gastrocnemius or tibialis anterior muscles. Unknown. Scekic-Zahirovic et al., 2016, Scekic-Zahirovic et al., 2017 Yes
B6;SJL-Tg(Prnp-FUS*R521C)3313Ejh/J Transgene injected into B6SJL oocytes. Maintained on C57BL/6, therefore subsequent generations have a higher percentage of C57BL/6. FUS FUS R521C Transgene encoding human FUS with the R521C mutation near the C-terminus. Flag-tagged construct driven by the Syrian hamster prion protein promoter. FUS: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Robust neurodegeneration in the anterior horn of the spinal cord, including about 50% loss of neurons by end stage. Prominent microgliosis and astrogliosis in the anterior horn at end stage. Very rare cytoplasmic FUS inclusions. A variety of motor impairments from a young age, including spastic paraplegia, abnormal hindlimb clasping, gait abnormalities, and impaired performance on the Rotarod. Growth retardation, muscle atrophy, DNA damage, and RNA splicing defects. Males may be sterile. The Jackson Lab: Stock# 026406; Cryopreserved Qiu et al., 2014 Yes
Tau-ON-hFUS-P525L C57Bl/6 FUS FUS P525L Transgene encoding myc-tagged human FUS-P525L with an upstream Lox-P flanked stop sequence was inserted into the MAPT locus by homologous recombination. These mice were crossed to the Prm1-Cre line for germline recombination to remove the stop sequence, allowing transgene expression. FUS: Knock-In Amyotrophic Lateral Sclerosis Progressive loss of spinal cord motor neurons associated with muscle denervation and reduced muscle fiber diameter. Gliosis in spinal cord. Abnormal mitochondrial morphologies. Mutant FUS mislocalized to cytoplasm. Deficits in wire hang test at 360 days. Progressive denervation of hind limb muscles. Unknown. Sharma et al., 2016 Yes
PrP-hFUS Tg (Prnp-FUS)WT3Cshw/J C57Bl/6/SJL founder mice backcrossed to C57Bl/6 FUS Transgene expressing wild-type human FUS with an N-terminal HA-tag. The mouse prion protein promoter (PrP) drives transgene expression. FUS: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia FUS accumulation in the cytoplasm, including cytoplasmic inclusions in neurons of the brain and spinal cord. Degeneration of spinal motor neurons (~60% by end stage) with astrogliosis and microgliosis. Severe motor impairment, starting as tremor and gait abnormalities, and progressing to impaired performance on the Rotarod and reduced locomotion. Ultimately hindlimb paralysis and inability to lift the pelvis. Born at Mendelian ratios. Focal muscle atrophy and signs of denervation in hindlimb muscles. Most founder lines did not propagate the transgene. The Jackson Lab: Stock# 017916; Cryopreserved Mitchell et al., 2012 Yes
Tau-ON-hFUS-R512C C57Bl/6 FUS FUS R521C Transgene encoding myc-tagged human FUS-R521C with an upstream Lox-P flanked stop sequence was inserted into the MAPT locus by homologous recombination. These mice were crossed to the Prm1-Cre line for germline recombination to remove the stop sequence, allowing transgene expression. FUS: Knock-In Amyotrophic Lateral Sclerosis Progressive loss of spinal cord motor neurons associated with muscle denervation. Gliosis in spinal cord. Mutant FUS mislocalized to cytoplasm. No data. Progressive denervation of hind limb muscles. Unknown. Sharma et al., 2016 Yes
PrP-PFN1-G118V C57Bl/6 PFN1 PFN1 G118V Untagged human PFN1-G118V cDNA is expressed by the mouse prion promotor (PrP). PFN1: Transgenic Amyotrophic Lateral Sclerosis Motor neuron loss in the spinal cord associated with muscle denervation and atrophy. Gliosis in spinal cord. Loss of corticospinal neurons of the motor cortex. Aggregates of TDP-43 in spinal motor neurons. Progressive motor impairments. Minor hind limb posture changes begin at 120 days. Paralysis occurred on average by 165-210 days. Denervation and atrophy of the gastrocnemius muscle in the hindlimb. Available through Mahmoud Kiaei Fil et al., 2017 Yes
ΔNLS4; tTA/TDP-ΔNLS, TDP-43-ΔNLS, tTA/ΔNLS B6;C3-Tg(tetO-TARDBP*)4Vle/J Transgene injected into fertilized eggs from C57BL/6J x C3HeJ. TARDBP These bigenic mice use the CAMKIIα promoter to drive expression of tetracycline transactivator (tTA) in forebrain neurons. The responder transgene is wild-type human TDP-43 minus the nuclear localization signal (NLS). Human TDP-43 is expressed constitutively unless suppressed by doxycycline. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Severe neuronal loss and gliosis in the dentate gyrus and deep cortical layers. Only very rare cytoplasmic aggregates of TDP-43 despite high levels of cytosolic protein. Degeneration of the corticospinal tract, but no lower motor neuron loss or muscle atrophy. A variety of motor, cognitive, and social deficits, including abnormal clasping response, impaired coordination on the Rotarod, decreased grip strength, impaired recognition and spatial memory, and decreased social behavior. Cognitive and motor impairments largely reversible in young mice following short-term transgene suppression. Downregulation of endogenous mouse TDP-43. No change in mortality up to 7 months of age. Mendelian ratios of offspring. The Jackson Lab: Stock# 014650; Live Igaz et al., 2011 Yes
rNLS8, regulatable NLS B6;C3-Tg(NEFH-tTA)8Vle Tg(tetO-TARDBP*)4Vle/J NEFH-tTA mice and tetO-hTDP-43ΔNLS line 4 mice were maintained on a mixed C57BL/6J x C3HeJ background. TARDBP These bigenic mice are the progeny of NEFH-tTA transgenic mice, in which the neurofilament heavy chain promoter drives expression of tetracycline transactivator (tTA), and tetO-hTDP-43ΔNLS (line 4) mice, which express a form of human TDP-43 lacking the nuclear localization signal in a tTA-dependent manner. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Widespread cytoplasmic inclusions of TDP-43 in the brain and spinal cord. Ubiquitin-positive inclusions, loss of endogenous mouse nuclear TDP-43, cortical atrophy, motor neuron loss, astrogliosis, and NMJ denervation. A variety of motor impairments, including hindlimb clasping, fine tremor in forelimb and/or hindlimb, progressive loss of grip strength, and decline in coordinated movement and balance. Progressive decrease in body mass from a peak two weeks off dox. Atrophy of hindlimb muscles at end-stage. Premature death (median survival 10.3 weeks off dox). Available through The Jackson Lab as single transgenics: Stock# 025397 and Stock# 014650; Live. See also double transgenic Stock# 028412; Live Walker et al., 2015 Yes
dNLS-FUS, deltaNLS-FUS C57Bl/6J FUS FUS ΔNLS Transgene encoding myc-tagged human FUS with a C-terminal truncation to delete the nuclear localization signal. Expression driven by the Thy1.2 promoter. FUS: Transgenic Amyotrophic Lateral Sclerosis The motor cortex exhibited gliosis, a loss of neurons, and ΔNLS-FUS aggregates positive for ubiquitin and p62.  Progressive motor impairments by 12 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as impaired performance on the Rotarod and hanging wire test. Reduced lifespan. Available through Daisuke Ito. Shiihashi et al., 2016 Yes
ΔNLS-FUS x TARDBP, deltaNLS-FUS x TAR4 C57Bl/6J FUS, TARDBP FUS ΔNLS A cross between the ΔNLS-FUS and TDP-43(WT) mice. The ΔNLS-FUS line contains a transgene expressing myc-tagged human FUS lacking the nuclear localization signal, driven by the Thy1.2 promoter. The TDP-43(WT) line contains a transgene that encodes wild-type human TARDBP, driven by the Thy-1 promoter. FUS: Transgenic; TARDBP: Transgenic Amyotrophic Lateral Sclerosis The motor cortex exhibited gliosis, a loss of neurons, and DNLS-FUS aggregates positive for ubiquitin and p62.  Progressive motor impairments by 8 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as impaired performance on the Rotarod and hanging wire test. Reduced lifespan. Available through Daisuke Ito. Shiihashi et al., 2016 Yes
Thy1.2-PFN1C71G/Prp-PFN1C71G FVB/N-Tg(Prnp-PFN1*C71G)22Zxu Tg(Thy1-PFN1*C71G)67Zxu/J FVB/NJ PFN1 PFN1 C71G Human PFN1-C71G cDNA with an N-terminal V5 tag is expressed by the human Thy1.2 promotor or mouse prion promotor (Prp). The mouse is homozygous for Thy1.2-PFN1-C71G and hemizygous for Prp-PFN1-C71G. PFN1: Multi-transgene Amyotrophic Lateral Sclerosis Motor neuron loss in the spinal cord associated with muscle denervation and atrophy. Gliosis in spinal cord. No neuronal loss in the cortex but neurodegeneration in medulla. Aggregates of PFN1, ubiquitin, and p62 form in motor neurons. Progressive motor impairments. Minor gate changes start by 4 month. Paralysis occurred on average by 7 months.Progressive decrease in body weight. Progressive decrease in body weight. Available as a triple transgenic through The Jackson Lab, Stock# 028608 Yang et al., 2016 Yes
PrP-hFUS*R495X transgenic line PX78, PrP-hFUS(R495X) line PX78 B6.Cg-Tg(Prnp-FUS*R495X)78Ljh/J Construct microinjected into C57BL/6 x SJL)F2 hybrid embryos and founders bred to FVB for 4+ generations. Subsequently back-crossed at JAX to create a C57BL/6 congenic. FUS FUS R495X These mice express a mutant form of human FUS carrying a truncation mutation near the C-terminus. The transgene is driven by the mouse prion protein promoter (Prp). The mutation abrogates the nuclear localization sequence and leads to cytoplasmic mislocalization of FUS. FUS: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Cytoplasmic mislocalization of human FUS, but no cytoplasmic inclusions or signs of neuronal loss. No overt behavioral abnormalities. By 8-12 months, EMG detected hindlimb muscular abnormalities including fibrillation potentials, muscle denervation, and a reduction in the number of motor units. Congenic available through The Jackson Lab: Stock# 019728; Cryopreserved Tibshirani et al., 2015 Yes
PWT17, PrP-hFUS(WT) line PWT17 B6.Cg-Tg(Prnp-FUS)17Ljh/J Construct microinjected into C57BL/6 x SJL)F2 hybrid embryos and founders bred to FVB for 4+ generations. Subsequently back-crossed at JAX to create a C57BL/6 congenic. FUS These mice overexpress wild-type human FUS. The transgene is driven by the mouse prion protein promoter (PrP). FUS: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia No overt neuropathology. Predominantly nuclear FUS. No inclusions or over neuronal loss. No overt behavioral abnormalities prior to becoming moribund around 203 days of age. Unexplained premature lethality about 203 days of age, proceeded by less than a week of ill-health. Congenic available through The Jackson Lab: Stock #020783; Cryopreserved Tibshirani et al., 2015 Yes
line 29, SOD1 (G37R) (hybrid background), G37R(29) SOD1, SOD1 G37R C57BL/6J x C3H/HeJ)F2 SOD1 SOD1 G37R Transgene carrying a 12kb DNA fragment encoding human SOD1 with the G37R mutation. Transgene driven by the human SOD1 promoter. SOD1: Transgenic Amyotrophic Lateral Sclerosis Degeneration of motor neurons in the spinal cord and brainstem characterized by extensive vacuolization. Astrogliosis. Wallerian degeneration of large myelinated axons. No overt upper motor neuron loss. Progressive motor impairment, beginning with reduced spontaneous movement, then tremors, limb weakness, poor grooming, and muscle wasting. Eventual paralysis of hindlimbs. Elevated dismutase activity in the brain and spinal cord (~7-fold). Unknown Wong et al., 1995 Yes
SOD1 (G85R) (line 148) Transgene injected into hybrid (C57BL/6J x C3H/HeJ)F2 embryos. SOD1 These transgenic mice express human SOD1 with the G85R substitution. 12 kb DNA sequence under the control of the human promoter and regulatory elements. SOD1: Transgenic Amyotrophic Lateral Sclerosis Degeneration of lower motor neurons, especially large-caliber axons, but also loss of motor neurons in the ventral horn. Extensive glial pathology in the spinal cord, including astrogliosis and microgliosis. Abundant SOD1 inclusions in astrocytes. Progressive motor impairment generally starting around 8 months of age with reduced grip strength in one hindlimb, rapidly spreading to other limbs and leading to paralysis. Unknown status of the hybrid line. A congenic line is available through The Jackson Lab: Stock# 008248; Cryopreserved Bruijn et al., 1997 Yes
G1H, High-copy SOD1-G93A, B6SJL.SOD1-G93A, Tg(hSOD1-G93A)1GUR mice, Gurney mice B6SJL-Tg(G93A-SOD1)1Gur/J C57Bl/6/SJL. SOD1 SOD1 G93A These transgenic mice express multiple copies of human SOD1 bearing the missense mutation G93A randomly integrated into chromosome 12 of the mouse. SOD1: Transgenic Amyotrophic Lateral Sclerosis Neuronal loss in the spinal cord (~50% loss in cervical and lumbar segments by end stage). Degeneration of upper motor neurons and brainstem nuclei. Swollen neurites, Gallyas silver-positive aggregates, vacuoles, and neuritic spheroids. Gliosis. Axonal degeneration and denervation of NMJ. Progressive motor impairment that starts as a shaking tremor. Proximal muscle weakness along with muscle atrophy, eventually leading to paralysis and death. Weight loss. The mutant SOD1 retains enzymatic activity. The Jackson Lab: Stock# 002726; Live. Scantox Neuro offers research services with this model. Gurney et al., 1994, Chiu et al., 1995 Yes
Prp-TDP43A315T B6.Cg-Tg(Prnp-TARDBP*A315T)95Balo/J C57BL/6J x CBA mice backcrossed to C57BL/6J. TARDBP TARDBP A315T This transgenic mouse expresses full-length human TARDBP with an N-terminal Flag tag and the A315T mutation. The transgene is driven by the mouse prion protein (PrP) promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis Minimal motor neuron loss in the spinal cord and cortex (but see Espejo-Porras et al., 2015 and Zhang et al., 2016). Ubiquitin-positive aggregates in upper and lower motor neurons. Rare TDP-43 aggregates. Astrocytosis in spinal cord and cortical layer V. Hyperexcitability of somatostatin interneurons. Axonal degeneration and ~ 20% loss of NMJ innervation (gel diet). Variable. Gait abnormalities, and impaired performance on the Rotarod. Also deficits in radial arm water maze, not due to deficits in swimming speed. Behavior potentially confounded by gut phenotype.  Severe dysfunction in the intestinal tract involving degeneration of neurons in the colon resulting in reduced motility though the ileocaecal area. GI obstruction is the likely cause of death unless the diet is modified with soft food or gel diet. The Jackson Lab: Stock# 010700; Live Wegorzewska et al., 2009, Hatzipetros et al., 2014 Yes
Baloh’s TDP-43, C57BL/6-CBA TDP-43 A315T The Prp-TDP43A315T transgene was introduced into oocytes from C57BL/6J x CBA mice. TARDBP TARDBP A315T Transgene encodes full-length, human, mutant TARDBP with the A315T mutation and an N-terminal Flag tag. The mouse prion protein (PrP) promoter drives transgene expression. TARDBP: Transgenic Amyotrophic Lateral Sclerosis Upper and lower motor neuron loss. Cytoplasmic aggregates of ubiquitinated proteins in motor neurons. Cortical gliosis. No cytoplasmic aggregates of TDP-43. Gait abnormalities around three months, developing into a characteristic “swimming gait” by four to five months. Born at normal Mendelian ratios. Grossly normal up to three months. Muscle pathology at end-stage, including atrophic muscle fibers. Generally milder phenotypes in females. No longer available on a C57BL/6J x CBA background Wegorzewska et al., 2009 Yes
C57BL/6J Tardbp Tardp Q331K CRISPR/Cas9 was used to introduce the p.Q331K mutation into the mouse Tardp gene. Tardbp: Knock-In Frontotemporal Dementia, Amyotrophic Lateral Sclerosis Unknown. Unknown. Available through Pietro Fratta or Abraham Acevedo-Arozena Fratta et al., 2018 Yes
LCDmut Tardbp M323K DBA/2J x C57BL/6J Tardbp Tardbp M323K This line was generated after screening DNA archives from two large-scale chemical mutagenesis projects (Acevedo-Arozena et al., 2008; Gondo et al., 2010) for mutations in Tardbp. Tardbp: Other Frontotemporal Dementia, Amyotrophic Lateral Sclerosis At 18 months of age, p62- and ubiquitin-positive inclusions in the ventral regions of the spinal cord, although apparently not in the cytoplasm of motor neurons. TDP-43 normally localized to the nucleus in 12-month mice. At 24 months, a 28 percent reduction in the number of motor neurons in the sciatic motor neuron pool, compared with control littermates. Grip strength in both male and female mice begins to decline at 12 months of age. By 24 months, there is a nearly 40 percent reduction in force measured in tibialis anterior muscles and a 15 percent reduction in motor units innervating the extensor digitorum muscle. Mice from original founders, on a hybrid DBA/2J x C57BL/6J background, are available from the RIKEN BioResource Center, BRC# GD000110. Fratta et al., 2018 Yes
RRM2mut Tardbp F210I DBA/2J x C57BL/6J Tardbp Tardp F210I This line was generated after screening DNA archives from two large-scale chemical mutagenesis projects (Acevedo-Arozena et al., 2008; Gondo et al., 2010) for mutations in Tardbp. Tardbp: Other Frontotemporal Dementia, Amyotrophic Lateral Sclerosis No spinal motor neuron loss, no p62- or ubiquitin-positive inclusions at 2 years in heterozygotes. Grip strength normal at 2 years in heterozygotes. Homozygous mutation is embryonic lethal. Muscle force, motor unit numbers normal at 2 years in heterozygotes. Mice from original founders, on a hybrid DBA/2J x C57BL/6J background, are available from the RIKEN BioResource Center, BRC# GD000108. Fratta et al., 2018 Yes
Transgene injected into C3H x C57Bl/6 embryos and then crossed with C57Bl/6. TARDBP TARDBP A315T Full-length human TDP-43 with the A315T mutation introduced by site-directed mutagenesis. The transgene is driven by the endogenous human promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Cytoplasmic inclusions of TDP-43, axonal changes, gliosis, no overt neuronal loss or loss of axons. Increased levels of cytotoxic 25 kDA C-terminal fragment of TDP-43. Age-associated cognitive and motor deficits as measured by the passive avoidance test and the Rotarod. Normal lifespan and fertility. Available through Jean-Pierre Julien Swarup et al., 2011 Yes
line 23 STOCK Tg(Prnp-TARDBP*A315T)23Jlel/J Transgene injected into fertilized hybrid B6SJLF1oocytes. Founders bred with CD1 to create hybrid CD1 and B6SJLF. TARDBP TARDBP A315T Transgene encodes full-length human TDP-43 with the A315T mutation. The mouse prion protein (Prp) promoter drives transgene expression. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia No overt neuronal loss in the brain or spinal cord. Ubiquitin-positive cytoplasmic inclusions in neurons of the ventral horn and brainstem. Astrocytosis. Cytoplasmic aggregates of TDP-43 are largely absent, although some phospho-TDP-43 inclusions at end-stage. Progressive motor impairment characterized by weakness, a decline in grip strength, and reduction in stride length. Weakness was usually more pronounced in the hindlimbs. Prior to motor deficits, mice exhibit increased fat storage, decreased lean muscle mass, and larger adipocytes in white fat. The Jackson Lab: Stock# 016143; Cryopreserved Stallings et al., 2010 Yes
Transgene injected into C3H x C57Bl/6 embryos. Founders backcrossed with C57Bl/6. TARDBP TARDBP G348C Full-length human TDP-43 with the G348C mutation introduced by site-directed mutagenesis. The transgene is driven by the endogenous human TARDBP promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Cytoplasmic inclusions of TDP-43 in neurons, axonal changes, denervated NMJs, gliosis, no overt neuronal loss or loss of axons. Increased levels of cytotoxic 25 kDA C-terminal fragment of TDP-43. Age-associated cognitive and motor deficits as measured by the passive-avoidance test, the Barnes maze, and the Rotarod. Impaired recovery after crush injury to the sciatic nerve (e.g., delayed recovery of motility and reduced axon regrowth). Normal lifespan and fertility. Available through Jean-Pierre Julien Swarup et al., 2011 Yes
TDP-43 M337V PrP (line 4) C57BL/6-Tg(Prnp-TARDBP*M337V)4Ptrc/J Transgene injected into fertilized C57BL/6 oocytes. Founders bred with B6. TARDBP TARDBP M337V Transgene expresses full-length human TARDBP with the M337V mutation, driven by the mouse prion protein (PrP) promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia No overt neuronal death. Microgliosis and astrogliosis. Abnormal mitochondria in the form of eosinophilic aggregates in spinal motor neurons. Widespread ubiquitination and accumulation of phospho-tau. Body tremors and gait difficulties before one month of age, leading to a “dragging” gait. An inability to right themselves precipitating euthanasia around one to two months of age. Reduced brain and body weight compared with non-Tg littermates. The Jackson Lab: Stock# 017604; Cryopreserved Xu et al., 2011 Yes
Mt-TAR6/6 Transgene injected into BL6/SJL oocytes. Founders crossed to C57BL6/J. TARDBP TARDBP M337V The Thy-1.2 promoter drives expression of a transgene encoding human TARDBP with the M337V mutation. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Neuronal loss in cortical layer V motor neurons, spinal anterior horn motor neurons, CA regions of the hippocampus, and thalamic neurons. Astrogliosis and microgliosis. Diffuse cytoplasmic ubiquitin in cortical and spinal motor neurons and hippocampus, but rare overt inclusions. Deformed mitochondria and fission deficits. Progressive motor impairment, involving a hunched posture, muscle twitches, and reduced mobility. Impaired Rotarod performance. Complete paralysis and premature death. Postnatal growth retardation and weight loss. Transgene induced downregulation in endogenous TDP-43. Increased caspase-3 expression. Ultrastructural mitochondria abnormalities. Unknown Janssens et al., 2013 Yes
Transgene introduced into C57Bl6/C3H oocytes. Founders crossed to C57/Bl6 for a minimum of four generations. TARDBP TARDBP Q331K Full-length human TDP-43 with the Q331K mutation driven by the mouse prion protein (Prp) promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Age-dependent lower motor loss, gliosis, NMJ abnormalities and loss. No TDP-43 aggregates or cytoplasmic mislocalization. A variety of motor impairments starting around 3 months of age including tremor, abnormal hindlimb clasping, decreased Rotarod performance, and a later decrease in grip strength. Unknown Arnold et al., 2013 Yes
TDP-43Q331K KI (Line 52) C57Bl/6J Tardbp Tardp Q331K CRISPR/Cas9 mutagenesis was used to introduce a point mutation equivalent to human Q331K into the mouse Tardp gene. Tardbp: Knock-In Frontotemporal Dementia, Amyotrophic Lateral Sclerosis No TDP-43- or tau-positive inclusions. No apparent loss of upper or lower motor neurons, but 25% decrease in number of parvalbumin-positive neurons in frontal cortex. Attention deficits in a five-choice serial reaction time task, memory deficits in a novel-object-recognition task, deficits in a marble-burying task. No apparent motor impairments. Gene-expression and splicing differences, compared with wild-type mice, including upregulation of Tardp, and altered splicing of Tardp, Sort1, Mapt. Available from Jemeen Sreedharan or Robert H. Brown Jr. White et al., 2018 Yes
Elliott, WT TDP-43 (line 4) B6SJL-Tg(Prnp-TARDBP)4Jlel/J Transgene injected into B6SJLF1 oocytes. Founders crossed with CD1 mice. TARDBP Transgene expressing full-length, wild-type, human TDP-43 driven by the mouse prion protein (Prp) promoter. Transgene integrated on X chromosome. TARDBP: Transgenic Amyotrophic Lateral Sclerosis No overt neuronal loss in the brain or spinal cord.  Progressive motor impairment (variable penetrance) starting with external rotation of one hind limb followed by bilateral weakness and low muscle tone. Relatively high TDP-43 expression in skeletal muscle. Myopathy, including variable muscle fiber size and disorganization of the muscle architecture. Ubiquitin-positive inclusions in skeletal muscle cells. Status of original hybrid unknown. This model is available on a B6SJL background through The Jackson Lab: Stock# 016201; Cryopreserved Stallings et al., 2010 Yes
Julien model, Wild-type TDP-43 Transgene injected into C3H x C57Bl/6 embryos. Founders crossed with C57Bl/6. TARDBP Full-length, wild-type, human TDP-43 driven by the endogenous human promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Some denervated NMJs, gliosis (microgliosis and astrogliosis), no overt neuronal loss or loss of axons. Mostly nuclear expression of TDP-43. Age-associated cognitive and motor deficits as measured by the passive avoidance test, Barnes maze, and Rotarod. Impaired recovery following crush injury to the sciatic nerve (e.g., delayed recovery of motility, reduced axon regrowth). Normal lifespan and fertility. Not available: extinct Swarup et al., 2011 Yes
WT-TAR4/4, WT-TAR4 B6;SJL-Tg(Thy1-TARDBP)4Singh/J Transgene introduced into BL6/SJL oocytes. Founders crossed to C57BL6/J. TARDBP Transgene encodes wild-type human TARDBP, driven by the murine Thy-1 promoter. The transgene integrated at locus 6qB3 in the mouse genome and does not interrupt any known gene. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Neuronal loss in the brain and spinal cord, including anterior cortex, CA3 hippocampus, Purkinje cells, and spinal cord. Astrogliosis and microgliosis especially in the anterior cortex. Widespread diffuse ubiquitin in neurons of the brain and spinal cord, including cytoplasmic and nuclear inclusions, some co-labeling for TDP-43. Progressive motor impairment, starting at postnatal day 14, with an abnormal hindlimb reflex. Gait abnormalities, including reduced stride length and impaired performance on the accelerating Rotarod. Quick progression to muscle fasciculation’s and spasms, followed by paralysis and premature death. Elevated anxiety at a young age. Size and weight of homozygotes lag behind non-Tg and hemizygous littermates. The Jackson Lab: Stock# 012836; Cryopreserved. The CRO Scantox Neuro offers research services with this model. Wils et al., 2010 Yes
Wild-type TDP-43 transgenic (line 3C), TDP-43PrP C57BL/6-Tg(Prnp-TARDBP)3cPtrc/J Transgene injected into fertilized C57BL/6 oocytes. Founders bred with B6. TARDBP Transgene expresses wild-type human TARDBP driven by the mouse prion protein (Prp) promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia No overt neuronal death, but degenerating neurites and axons, gliosis, and vacuolization of myelin. Abnormal aggregates of mitochondria present as eosinophilic aggregates in spinal motor neurons. Dendritic spine loss in the hippocampus. Homozygous mice develop body tremors and gait impairments leading to a “swimming gait” and severe motor deficits requiring euthanasia. Early reductions in body and brain weight in homozygous mice. Reduced dendritic spines in the hippocampus and lower mRNA levels of synaptic markers. The Jackson Lab: Stock# 016608; Cryopreserved Xu et al., 2010 Yes
WT-TAR6/6, TAR6/6 Transgene introduced into BL6/SJL oocytes. Founders crossed to C57BL6/J. TARDBP Transgene encodes wild-type human TARDBP, driven by the murine Thy-1.2 promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Accumulation of transgenic and C-terminal fragments of TDP-43 in the cytoplasm, upper and lower motor neuron loss, astrogliosis, and microgliosis. Motor impairments as early as 6 weeks, reduced anxiety and disturbed nest-building behavior. Early death—average survival is 6.7 months. The CRO Scantox Neuro offers research with TAR6/6 mice. Wils et al., 2010, Scherz et al., 2018 Yes

44 Visualizations

Sex-specific differences

  • Cortical Neuron Loss
  • Lower Motor Neuron Loss
  • Cytoplasmic Inclusions
  • Gliosis
  • NMJ Abnormalities
  • Muscle Atrophy
  • Motor Impairment
  • Body Weight
  • Premature Death

AAV-GFP-(GA)50

  • Observed
  • No Data
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • No Data

At 6 months, neuron loss observed in cortex, including layer V of motor cortex.

No data.

Neuronal poly(GA)- and ubiquitin-positive inclusions already present at 4-6 weeks; rare TDP-43-positive inclusions.

Astrogliosis, but not microgliosis, in cortex and hippocampus, seen at 6 months.

No data.

No data.

Deficits in tail-suspension and rotarod tests, seen at 6 months.

Decreased body weight in males, but not females, seen at 6 months.

No data.

AAV-GFP–(GR)100

  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Absent
  • No Data

Fewer cortical neurons than controls, observed as early as 6 weeks of age.

Not observed up to 6 months of age.

Very rare TDP-43 inclusions, observed at 6 months.

Astrogliosis and microgliosis in cortex and hippocampus, observed at 6 weeks.

No data.

No data.

Progressive motor deficits, seen in open-field, rotarod, rod-walk, and wire-hang tests.

Normal at 6 months of age.

No data.

C9-BAC500 (Brown)

  • Absent
  • Absent
  • Observed
  • Absent
  • Absent
  • No Data
  • Absent
  • Absent
  • Absent

Not observed.

Not observed.

No cytoplasmic mislocalization, or aggregation of TDP-43 in the motor cortex. However, dipeptide repeats accumulated at advanced age and formed small perinuclear inclusion bodies positive for poly-GP.

No signs of increased activation of microglia or astrocytes in the brain or spinal cord.

No difference in denervation of neuromuscular junctions at 24 months of age. No difference in motor or sensory spinal nerve root axon number or morphology.

Muscle histology has not been reported, but no overt muscle atrophy was observed.

No overt motor deficit as measured by the Rotarod and grip strength.

Non-significant trend for male C9BAC mice to be heavier than non-Tg controls. Female data have not yet been reported.

Normal lifespan beyond 2 years in male mice. Female data have not yet been reported.

C9-BACexp (Baloh/Lutz)

  • Absent
  • Absent
  • Observed
  • Absent
  • Absent
  • Absent
  • Absent
  • Absent
  • Absent

Not observed.

Not observed.

RNA foci throughout the nervous system starting at 3 months of age. Foci comprised of RNA transcripts in both the sense and antisense directions. Age-associated formation of dipeptide aggregates, e.g., poly-GP.

No increase in GFAP staining in the brain and spinal cord compared with non-Tg controls, even at 18 months of age.

Not observed.

Not observed.

No abnormalities in grip strength, Rotarod performance, or open-field testing at a young age (3 months) or advanced age (18 months), compared with non-Tg controls.

No abnormalities in body weight at a young age (3 months) or advanced age (18 months) compared with non-Tg controls.

Normal lifespan.

C9orf72 Knock-out

  • Absent
  • Absent
  • Absent
  • Absent
  • Absent
  • Absent
  • Observed
  • Absent
  • Absent

Not observed.

Not observed.

Not observed.

Not observed.

Not observed.

Not observed.

Reduced activity on open-field test. No abnormalities in grip strength or Rotarod performance.

Not observed.

Not observed.

C9ORF72(AAV)(G4C2)149

  • Observed
  • No Data
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • No Data
  • No Data

Cortical neuron loss by 6 months.

No data.

Cytoplasmic inclusions containing dipeptide repeat proteins (DPRs) derived from sense RNA seen in the cortex, hippocampus, cerebellum, and spinal cord; inclusions containing DPRs produced from antisense transcripts seen in the cortex and occasionally in the hippocampus.

Astrogliosis in the cortex by 3 months.

No data.

No data.

Deficits in the hanging wire test emerge between 3 and 6 months.

No data.

No data.

C9ORF72(AAV)(G4C2)66

  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • No Data

Compared with mice expressing 2-repeats, the 66-repeat mice had 17 percent fewer neurons in the cortex at 6 months of age and 11 percent fewer Purkinje cells in the cerebellum. At this age neurons in the hippocampus and thalamus were not affected.

At 6 months, neuronal loss in the spinal cord was not detected.

By 6 months, inclusions of C9RAN dipeptides were present in neurons of the cortex and hippocampus, and to a lesser extent in the cerebellum and spinal cord. Inclusions contained polyGA, polyGP, and polyGR dipeptides and were largely ubiquitin-positive.

Astrogliosis in the cortex by 6 months.

No data.

No data.

At 6 months, 66-repeat mice perform as well as 2-repeat mice on the Rotarod on the first day of testing. However, they fail to improve during subsequent trials, suggesting impairments in coordination and/or motor learning.

At 6 months females had a lower body weight than mice expressing 2-repeats. Body weight did not differ in males.

No data.

CamKII;(GR)80

  • Observed
  • No Data
  • Absent
  • Observed
  • No Data
  • No Data
  • Absent
  • Absent
  • No Data

Neuron loss in the cortex, beginning between 3 and 6 months of age.

No data, but note that the transgene is not expressed in these neurons.

No TDP-43 inclusions seen in mice studied up to 8 months of age.

Microgliosis and astrogliosis evident at 6 and 9 months, respectively.

No data.

No data.

No difference between CamKII;(GR)80 mice and CamKII-tTA control mice up to 9 months of age.

No difference between CamKII;(GR)80 mice and CamKII-tTA control mice up to 11 months of age.

No data.

Endogenous Sod1 D83G

  • Observed
  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • Observed
  • Observed
  • Observed

Neuronal numbers comparable to wild-type at 15 weeks, but about 20 percent loss of upper motor neurons by 29 weeks. Neurons in layer V of the motor cortex appeared selectively vulnerable.

Neuronal numbers comparable to wild-type at 6 weeks, but loss occurred by 15 weeks. The neuronal loss then stabilized; it was not more severe at 52 weeks of age.

Not observed.

Gliosis, of both astrocytes and microglia, was evident in the spinal cord by 15 weeks. It was further elevated at 52 weeks.

Denervation of a hindlimb muscle, the extensor digitorum longus, was detected by 52 weeks of age, and a decreased number of motor units in the EDL muscle.

Muscle atrophy was not reported, although changes to the muscle composition and histochemistry were observed.

Both male and female mice develop a variety of progressive motor symptoms. Grip strength was reduced at 6 weeks of age. Tremors developed by about 5 months of age. Rotarod performance was impaired, at 23 weeks in females and 67 weeks in males.

Homozygous mice, both male and female, showed reduced body weight by 4 weeks of age in contrast to wild-type littermates. Loss of excessive body weight was the primary factor leading to euthanasia.

Males reach end-stage sooner than females (495 ± 22 versus 588 ± 24 days). Animals were sacrificed when weight loss exceeded 20 percent of maximum weight, in accordance with animal-use guidelines. This is likely explained by the development of hepatocellular carcinomas due to SOD1 loss of function.

FUS-R521C

  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

No detectable loss of cortical neurons; however, neurons in the sensorimotor cortex show reduced dendritic complexity and reduced synaptic density.

No detectable difference in spinal motor neurons at P0. At P16, about 20% loss of ChAT-positive neurons in the anterior horn of cervical spinal cord. At P30-P60, about 50% loss of anterior horn neurons. Remaining motor neurons show reduced dendritic complexity and synaptic density.

Less than 10% of spinal motor neurons have cytoplasmic FUS inclusions.

Prominent increase in microgliosis and astrogliosis in the anterior horn of the spinal cord by end stage.

Reduced innervation of neuromuscular junctions in the diaphragm.

The majority of mice have severe skeletal muscle atrophy in the hindlimb by end stage.

Early postnatal motor impairment, including abnormal hindlimb clasping when lifted by the tail, gait abnormalities, and impaired Rotarod performance.

Early postnatal growth is retarded, and the mice experience progressive loss of body weight.

The majority of mice in the N1F1 generation reached end stage and were sacrificed by postnatal day 100. Mice in subsequent generations live longer: about 40% reach end stage by postnatal day 200.

FUSDelta14 Knock-in

  • No Data
  • Observed
  • Absent
  • No Data
  • Observed
  • No Data
  • Observed
  • No Data
  • Observed

No data.

No lower motor neuron loss at 3 months but 14% reduction in the number of motor neurons in lumbar spinal cord at 12 months and 20% reduction by 18 months.

No increase in the number of spinal motor neurons that contain p62- or ubiquitin-positive inclusions in aged FUSDelta14 mice compared with aged wild-type mice.

No data.

Reduction in the number of intact neuromuscular junctions (fully innervated endplates) in hindlimb lumbrical muscles by 18 months of age.

No data.

Normal motor activity at 3 months of age but impaired hindlimb function by 15 months.

No data.

Reduced survival starting at 19 months of age.

FUSΔ14 (FUSd14)

  • Absent
  • Absent
  • Observed
  • Absent
  • No Data
  • No Data
  • Absent
  • No Data
  • No Data

Not observed.

Not observed.

Neuronal cytoplasmic inclusions were present by 3 months of age in the cerebral cortex. Inclusions occurred in about 20% of neurons and often co-labeled with ubiquitin.

No obvious astrogliosis or microglial activation at 3 months of age in the cerebral cortex.

No data.

No data.

When the mice were sacrificed at 3 months of age, they appeared healthy and displayed no obvious motor phenotype.

No data.

No data.

FusΔNLS

  • No Data
  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • Observed
  • Absent
  • Absent

No data.

Approximately 30% reduction of motor neuron numbers in the dorsal spinal cord.

Ubiquitin pathology was observed in motor neurons, but p62 inclusions were not.

Slight increase in oligodendrocytes in the spinal cord white matter.

Fibrillation and fasciculation potentials were observed in the gastrocnemius or tibialis anterior muscles. There was also a reduction in compound muscle action potential amplitude.

No data.

By 10 months, mice demonstrated irregular walking patterns and reduced hang time on the inverted grid test. No deficits in grip strength or rotarod performance. Paralysis was not observed.

By 22 months, no weight loss was observed.

Life span was not altered.

hFUS (+/+) (PrP-hFUS)

  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

In the brain, overt neuronal loss was absent at end stage (~11 weeks).

By end stage (~11 weeks), homozygous mice had lost about 60 percent of α-motor neurons in the anterior horn of the lumbar spinal cord.

By end stage, cytoplasmic FUS inclusions, described as “granular” and “globular,” develop in the spinal cord of homozygous mice. Ubiquitin-positive inclusions also develop, but do not co-localize with FUS inclusions. Neurons in the brain also develop “granular” and “skein-like” FUS inclusions.

By end stage (~11 weeks), homozygous mice had microgliosis and astrogliosis in the anterior horn of the spinal cord and in the white matter of the dorsal columns. Reactive gliosis was absent in the brain, despite cytoplasmic inclusions of FUS in some neurons.

Homozygous mice had about 20 percent fewer functional motor units in the extensor digitorum longus muscle as estimated by neurophysiological assessment.

Muscle histology from end stage (~11 weeks) homozygous mice showed focal muscle atrophy in hindlimb muscles.

Homozygous mice exhibited motor symptoms at four weeks of age, starting with a tremor and mild signs of hindlimb dysfunction, including gait abnormalities. Motor symptoms progressed quickly, ultimately developing into hindlimb paralysis.

Homozygous mice fail to gain weight normally starting about four weeks of age. Their body weight declines in subsequent weeks, often precipitating euthanasia.

Homozygous mice were euthanized between 10 and 13 weeks of age when they developed severe motor impairment or lost 25 percent of their body weight. Average survival was 82 ± 12 days.

hFUS-P525L

  • No Data
  • Observed
  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • Absent

No data.

Progressive loss of motor neurons at lumbar level 5.

No FUS inclusions were observed.

Astrocytosis and microgliosis were observed in the spinal cord.

Progressive denervation of hindlimb muscles. Decreased density of synaptic vesicles and mitochondria with normal morphologies. Altered electrophysiological properties.

Reduced fiber diameter in the tibialis anterior muscle.

Deficits in wire hang test at 360 days.

No data.

Not observed by 360 days.

hFUS-R521C

  • No Data
  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • No Data
  • Absent

No data.

Progressive loss of motor neurons at lumbar level 5.

No FUS inclusions were observed.

Astrocytosis and microgliosis were observed in the spinal cord.

Progressive denervation of hind limb muscles. 

No data.

No data.

No data.

Not observed by 360 days.

hPFN1-G118V

  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

At 202 days, there was a decrease in the number of corticospinal neurons of the motor cortex.

Progressive loss of ventral horn neurons from 165 through 202 days of age.

Spinal cord motor neurons had TDP-43 puncta.

Astrocytosis and microgliosis were observed in the spinal cord at end stage.

Denervation of gastrocnemius muscle at end stage. Muscle action potential also had reduced amplitude.

At 165 days, hind limb muscle atrophy was observed.

Progressive motor impairments began ~ 120 days. Mice demonstrated tremors, limb clasping, muscle weakness, gait abnormalities, as well as reduced locomotion and decreased performance on the Rotarod. 

Body weight peaked ~ 150 days and then progressively decreased.

Mice were sacrificed at an average of 202 days when they were unable to right themselves. Females on average reached 191 days while males attained 213 days.

hTDP-43ΔNLS

  • Observed
  • Absent
  • Absent
  • Observed
  • No Data
  • Absent
  • Observed
  • No Data
  • Absent

Severe neuronal degeneration in the dentate gyrus and deep layers of the neocortex. Other regions, such as the hippocampal CA1 subfield and olfactory bulb, were relatively resistant to neurodegeneration. Approximately 50 percent of dentate gyrus neurons were lost one month after the transgene was activated.

Not observed.

High levels of cytosolic TDP-43 but only very rare aggregates (observed in less than 1 percent of cortical neurons and even rarer in other brain regions, such as the hippocampus and striatum).

Severe astrogliosis and microgliosis in areas affected by neurodegeneration, including cortical and hippocampal regions, as well as the corticospinal tract.

Unknown.

Not observed.

Spastic motor impairment indicated by an abnormal clasping response as early as one week after transgene induction. A variety of motor deficits develop by one month after transgene induction, including impaired coordination on the Rotarod and decreased grip strength.

Unknown.

Not observed.

NEFH-tTA x hTDP-43ΔNLS

  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

Decreased cortical thickness indicative of neuronal degeneration beginning at four weeks off dox. By end stage, rNLS8 mice had significantly smaller brains than non-Tg littermates.

rNLS8 lost motor neurons in the lumbar spinal cord by six weeks off dox.

Cytoplasmic inclusions of TDP-43 occur as early as one week off dox in neurons in the brain. Inclusions accumulate over time and are present in many brain regions, including the motor cortex. TDP-43 inclusions are relatively rare in the spinal cord. Ubiquitin-positive inclusions are also seen.

Astrogliosis develops in many brain regions, including layer V of the motor cortex.

Denervation of the hindlimb muscle tibialis anterior was detectable by four weeks off dox, that is, two weeks prior to detectable loss of lower motor neurons.

At end-stage, rNLS8 mice exhibit gross muscle atrophy of the hindlimb muscles tibialis anterior and gastrocnemius.

rNLS8 mice develop a variety of motor impairments, starting with a deficit in hindlimb clasping and a fine tremor in the forelimb and/or hindlimb. They also develop progressive loss of grip strength (as measured by the wire-hang test) and a progressive decline in coordinated movement and balance (as measured by the accelerating Rotarod).

Body mass peaked at approximately 7 weeks of age (i.e., two weeks off dox) and then progressively dropped. Excessive loss of body weight (>30% decrease from peak weight) often defined end-stage.

rNLS8 mice die prematurely. They reach end-stage 8-18 weeks off dox, with a median survival of 10.3 weeks off dox.

PFN1-C71G

  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

No neuronal loss in the cortex but neurodegeneration in medulla.

By 4 months there was a loss of cervical motor neurons and an increase in degenerating axons.

Cytoplasmic inclusions of PFN1, ubiquitin, and p62 in motor neurons around 6 months.

Microgliosis and astrogliosis observed in the dorsal horn by 5 months.

Denervation of gastrocnemius muscle occurs by 5 months.

Muscle atrophy in lower hind limb occurs by 6 months.

By 4 months, mice began showing minor gate changes and at 5-6 months they began demonstrating progressive deficits in Rotorod performance, vertical behaviors, and grip strength. 

Body weight peaked at 4-6 months and then progressively decreased.

Mice were sacrificed when they were incapable of locomotion following the paralysis of two or more limbs which occurred around 7 months of age.

PrP-hFUS (R495X)

  • Absent
  • Absent
  • Absent
  • No Data
  • Observed
  • No Data
  • Absent
  • No Data
  • Observed

Not observed.

Not observed.

Despite high levels of cytoplasmic FUS, neuronal inclusions were not observed.

No data.

A number of abnormalities were detected in the hindlimb musculature by electromyography (EMG). These phenotypes were detectable by 8-12 months of age and included fibrillation potentials, muscle denervation, and a reduction in the number of motor units.

No data.

Not observed.

No data.

Hemizygous mice sporadically developed intestinal swelling leading to premature death (mean survival 118 days). Homozygous mice were more severely affected (50 percent of the original cohort died around 59 days of age).

PrP-hFUS (WT)

  • No Data
  • No Data
  • Absent
  • No Data
  • Absent
  • No Data
  • Absent
  • No Data
  • Observed

No data.

No data.

Not observed.

No data.

Not observed.

No data.

Not observed.

No data.

Hemizygous mice die prematurely following a brief illness characterized by poor feeding. Mean survival of hemizygotes ~203 days.

SOD1 (G37R)

  • Absent
  • Observed
  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

Upper motor neuron loss was not observed, although vacuolization occurred in brainstem neurons.

Motor neurons in the spinal cord and brainstem degenerated with overt neuronal loss in the ventral horn in some regions of the spinal cord by 19 weeks. The degenerative process involved extensive vacuolization.

Not observed.

Astrogliosis occurs in the spinal cord by 11 weeks of age, becoming more severe with age.

Denervated endplates have been observed.

Loss of motor axons, denervated endplates, atrophy of muscle fibers, and fiber type grouping observed by end-stage.

Motor impairment at 4-6 months, beginning with reduced spontaneous movement, then tremors, limb weakness, and poor grooming. Eventual paralysis of the hindlimbs.

Loss of body weight is observed.

Mice survive about 6 to 8 months.

SOD1-G85R (hybrid)

  • No Data
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

Unknown.

Extensive degeneration of large spinal axons coincident with the onset of clinical symptoms. By end stage, motor neurons in the ventral horn are lost.

Astrocytic inclusions occur early, about 6 months of age. The inclusions are immunoreactive for SOD1 and ubiquitin.

Astrogliosis and microgliosis are observed in the spinal cord starting around 6.5 months of age, and become more severe with age.

Denervation of muscle fibers is observed.

Hemizygous mice develop muscle weakness around 9 months of age, coincident with atrophy and denervation of muscle fibers.

Progressive motor impairment generally starting around 8 months with reduced grip strength in one hindlimb, rapidly spreading to other limbs and leading to paralysis within about two weeks.

Hemizygous mice start to lose weight at about 9 months of age.

End stage is characterized by paralysis at about 10 months of age.

SOD1-G93A (hybrid) (G1H)

  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

Although outright upper motor neuron loss is absent or rare, degenerative signs (e.g., swollen neurites, Gallyas-positive aggregates, vacuoles, and neuritic spheroids) have been shown in motor regions of the cerebral cortex by five months of age.

Up to 50% loss of motor neurons in the cervical and lumbar segments of the spinal cord at end stage.

Inclusions accumulate in spinal motor neurons starting around 82 days of age. Inclusions generally take the form of spheroids or Lewy-body-like inclusions and commonly include a variety of neuronal intermediate filament proteins. TDP-43-positive inclusions are not present.

Gliosis, including the proliferation of reactive microglia and astrocytes, develops in parallel with motor neuron degeneration in the spinal cord.

Neuromuscular junctions degenerate around 47 days of age; fast-fatiguable motor neurons are affected first.

Longitudinal MRI has shown reduced muscle volume as early as 8 weeks of age. Atrophy is progressive. Skeletal muscle is affected, including limb and diaphragm.

Signs of motor impairment begin at about 3 months of age with a shaking tremor that leads to paralysis.

One of the first signs of illness is a slowing of growth and a plateauing of weight.

G1H mice reach end-stage disease by 5 months of age. Females typically survive longer than males.

TARDBP (A315T) (congenic)

  • No Data
  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

These mice lose corticospinal tract axons, but outright loss of cortical neurons has not been reported in the model. When crossed with a Thy-1YFP model to label layer 5 pyramidal neurons, mice expressing TDP-43 (A315T) had fewer neurons at 15 weeks of age than YFP littermate controls (Zhang et al., 2016).

Most studies reported no lower motor neuron loss. One study observed 20% loss of large ventral horn neurons, possibly dependent on diet and how long the mice live in an individual colony.

Ubiquitinated inclusions in the cytoplasm of spinal motor neurons and cortical layer V neurons. No evidence for cytoplasmic TDP-43 inclusions.

Reports of astrocytosis in cortical layer 5 and in the spinal cord, as well as microgliosis in the spinal cord.

Denervation of neuromuscular junctions at end stage (~11% on normal diet; ~20% loss on a gel diet).

Atrophy of gastrocnemius muscle (gel diet).

Deficits have been reported in nonspecific measures of strength and coordination such as the Rotarod (males and females) and hanging-wire test (males). A severely impaired gait (“swimming gait”) was observed in mice fed a gel diet.

Weight loss is a consistent feature. Potentially confounded by severe gut phenotype.

Survival is limited by severe gastrointestinal dysfunction and can be prolonged with a gel diet. Lifespan varies, but in general on a standard diet males live about 3 months and females about 6 months.

TARDBP (A315T) (hybrid)

  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • Observed
  • Observed
  • Observed
  • Observed

By end-stage, neuronal numbers in layer 5 of the motor cortex are decreased with about 50 percent loss of corticospinal tract axons.

By end-stage, ~20% loss of motor neurons in the L3-L5 region of the spinal cord.

By end-stage, cytoplasmic inclusions of ubiquitinated proteins in layer 5 neurons of motor, sensory, and cingulate cortex. Ubiquitin aggregates in ventral horn neurons. TDP-43 inclusions were rare.

By end-stage, selective increase in GFAP immunoreactivity in cortical layer 5.

Unknown.

By end-stage, atrophic muscle fibers were observed.

Gait abnormalities around three months of age, developing into a characteristic “swimming gait” by four to five months.

Weight was comparable to non-Tg mice at birth. By 4.5 months transgenic mice began to lose weight.

Survival for about 5 months (154 ± 19 days) before dying spontaneously or being euthanized. It was not reported if this analysis includes males, females, or both.

Tardbp Q331K Knock-In

  • No Data
  • No Data
  • No Data
  • No Data
  • No Data
  • No Data
  • No Data
  • No Data
  • No Data

No data.

No data.

No data.

No data.

No data.

No data.

No data.

No data.

No data.

Tardp LCDmut

  • No Data
  • Observed
  • Observed
  • No Data
  • Observed
  • No Data
  • Observed
  • No Data
  • Absent

No data.

28 percent reduction in the number of motor neurons in the sciatic motor neuron pool, compared with non-transgenic littermates.

At 18 months of age, p62- and ubiquitin-positive inclusions are found in the ventral regions of the spinal cord, although these inclusions do not appear to be located in the cytoplasm of motor neurons.

No data.

By 24 months, a 15 percent reduction in motor units innervating the extensor digitorum muscle.

No data.

Grip strength in both male and female mice begins to decline at 12 months of age. By 24 months, there is a nearly 40 percent reduction in force measured in tibialis anterior muscles.

No data.

Do not exhibit premature death, at least until 24 months of age.

Tardp_RRM2mut

  • No Data
  • Absent
  • Absent
  • No Data
  • Absent
  • No Data
  • Absent
  • No Data
  • Absent

No data.

Not observed at 2 years.

Not observed at 2 years.

No data.

Not observed at 2 years.

No data.

Not observed at 2 years.

No data.

Homozygous mutation is embryonic lethal.

TDP-43 (A315T)

  • Absent
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • No Data
  • Absent

Not observed.

Not observed.

Cytoplasmic accumulation of TDP-43 was observed by 10 months of age in the spinal cord. Furthermore, cytoplasmic aggregates were observed and often co-localized with ubiquitin. These inclusions are not detected at three months of age.

Progressive gliosis of both astrocytes and microglia, starting at a young age (by 3 months) in the brain and spinal cord.

Unknown.

Unknown.

At 38 weeks of age, mice develop impairments on the accelerating Rotarod relative to non-Tg littermates.

Unknown.

Not observed.

TDP-43 (A315T) (line 23)

  • Absent
  • Absent
  • Observed
  • Observed
  • No Data
  • Observed
  • Observed
  • Observed
  • Observed

Not observed.

Not observed.

Ubiquitin-positive cytoplasmic inclusions in neurons of the ventral horn and brainstem. Cytoplasmic aggregates of TDP-43 are largely absent, although rare phospho-TDP-43 inclusions were observed, especially at end-stage.

Mice exhibiting muscle weakness had astrocytosis in the ventral horn of the spinal cord.

Unknown.

Atrophy of muscle fibers in the quadriceps muscle of weak mice observed by day 44.

Progressive motor impairment, characterized by weakness, a decline in grip strength, and reduction in stride length. Weakness was usually more pronounced in the hindlimbs.

Progressive weight loss.

Line 23 mice survived about 2.5 months, mean survival 75 days. It was not reported whether this survival analysis includes males, females or both. Colony at Jackson Labs has longer mean survival.

TDP-43 (G348C)

  • Absent
  • Absent
  • Observed
  • Observed
  • Observed
  • No Data
  • Observed
  • No Data
  • Absent

Not observed.

Not observed.

Cytoplasmic accumulation of TDP-43 was observed by 10 months in the spinal cord. Cytoplasmic aggregates occurred and often co-localized with ubiquitin. These inclusions are not detected at 3 months of age.

Progressive gliosis of both astrocytes and microglia, starting at a young age (by 3 months) in the brain and spinal cord.

In 10-month-old mice, approximately 10% of NMJs in the gastrocnemius muscle were denervated, with another 20% partially denervated.

Unknown.

Performance on the Rotarod was comparable to non-Tg littermates until 36 weeks of age, and became progressively worse with age.

Unknown.

Normal lifespan.

TDP-43 (M337V)

  • Absent
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed

Not observed.

Not observed.

TDP-43 protein was largely nuclear, although some cytoplasmic TDP-43 was also observed. Some mild cytoplasmic inclusions were reported.

Reactive astrocytes and activated microglia proliferate in the spinal cord and brainstem.

No data.

No data.

Body tremors apparent by day 21 and the mice had difficulty recruiting their hindlimbs, leading to an irregular gait pattern, described as “dragging.”

 

By one month of age, homozygotes have reduced body weight compared to non-Tg littermates.

 

70% mortality of homozygotes by around one month of age.

TDP-43 (M337V) (Mt-TAR6/6)

  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed

Severe neuronal loss in all CA regions of the hippocampus of homozygous mice. Neuronal loss was also observed in layer V cortical neurons and thalamic neurons.

Neuronal loss was observed in the spinal cords of homozygous mice.

Some homozygous mice developed cytoplasmic inclusions in layer V cortical neurons. These were often, but not always, ubiquitin–positive. They were not universally observed, even in end-stage mice.

Elevated astrogliosis and microgliosis compared with non-Tg controls, especially in the motor cortex and spinal cord. Gliosis in the hippocampus was seen at end stage.

Unknown.

Unknown.

Motor impairment developed quickly, by 11 days of age in homozygous mice, starting with an abnormal clasping reflex. They also develop a hunched posture, muscle twitches, and reduced mobility. Paralysis developed within days, leading to death. Hemizygotes do not develop motor symptoms until about one year of age, and impairment varied from mouse to mouse.

Early postnatal growth retardation in homozygous mice. By day 17 their average body weight is about half that of non-Tg controls.

Homozygous mice survived an average of just 17 days. In contrast, hemizygous Mt-TAR6 mice lived up to 24 months (average survival ~16.4 months).

TDP-43 (Q331K)

  • No Data
  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • Observed
  • No Data
  • No Data

Unknown.

Age-dependent loss of lower motor neurons in the lumbar spinal cord. Loss is detectable as early as 2 months of age and is more pronounced by 10 months.

TDP-43 in the brain and spinal cord was predominantly nuclear. Cytoplasmic TDP-43 aggregates were absent.

Elevated astrogliosis and microgliosis in the ventral horn of spinal cord by 10-12 months of age compared with non-Tg controls.

Reduction in neuromuscular junction endplates by 10-12 months of age. Remaining NMJs often had a “bleb-like” appearance.

Muscle fiber abnormalities including centralized nuclei and damage by 10-12 months of age.

Tremor, abnormal hindlimb clasping, impaired performance on the Rotarod were detectable starting around 3 months of age. Reduced grip strength occurred later.

Unknown.

Unknown.

TDP-43 (Q331K) Knock-In (Line 52)

  • Observed
  • Absent
  • Absent
  • No Data
  • Absent
  • No Data
  • Absent
  • Observed
  • Observed

25% loss of parvalbumin-positive neurons at 5 months.

Not observed.

Not observed.

Unknown.

Not observed.

Unknown.

Not observed.

Increased body weight.

Mutation may be deleterious to male embryos.

TDP-43 (WT) (Elliott)

  • Absent
  • Absent
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed
  • Observed

Not observed.

Not observed.

Cytoplasmic ubiquitin-positive inclusions in skeletal muscle cells. Some TDP-43 inclusions, too.

No data.

No data.

An analysis of the quadriceps muscle, showed signs of myopathy, including variable muscle fiber size and disorganization of the muscle architecture.

Progressive motor impairment starting with external rotation of one hind limb followed by bilateral weakness and low muscle tone. Variable penetrance of this phenotype.

Progressive weight loss.

The mean survival of hemizygous mice was 109 days (it is not clear if this value represents males, females, or both).

TDP-43 (WT) (Julien model)

  • Absent
  • Absent
  • Absent
  • Observed
  • Observed
  • No Data
  • Observed
  • No Data
  • No Data

Not observed.

Not observed.

Primarily nuclear localization of human TDP-43.

Gliosis, both microgliosis and astrogliosis, occur early in the brain and spinal cord. Reactive glia were detected as early as 3 months of age, with more by 10 months.

Some NMJ denervation was observed by 10 months of age. About 5% of NMJs at the gastrocnemius muscle were denervated, with another 20 percent partially denervated.

No data.

Decreased performance on the accelerating Rotarod at 42 weeks of age. Further impairment at 52 weeks.

No data.

No data.

TDP-43 (WT) (Kumar-Singh)

  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed

In homozygous mice, quantitative loss of neurons occurs in the motor cortex compared with non-Tg littermates. Both superficial and deep cortical layers of the anterior cortex are affected.

By day 18, homozygous mice exhibited about 25 percent loss of motor neurons in the lumbar spinal cord compared with non-Tg littermates.

Homozygous mice developed cytoplasmic inclusions in the brain and spinal cord, many of which were ubiquitin-positive. A minority of inclusions co-labeled with TDP-43. Ultrastructural analysis revealed ubiquitin–negative cytoplasmic inclusions in anterior horn neurons to be abnormal accumulations of mitochondria.

Astrogliosis and microgliois especially in cortical layer V of the anterior cortex, including motor and somatosensory cortex, and in the spinal cord.

No data.

No data.

Homozygous mice exhibit an abnormal clasping reflex by postnatal day 14. Other early motor deficits include a shortened stride, a wide stance, and frequent stumbling. By day 18, reduced performance on the Rotarod. Complete paralysis occurs ~10 days after onset.

Size and weight of homozygous mice lag behind hemizygotes and non-Tg littermates.

Homozygous mice survive an average of just 24 days. In contrast, hemizygous mice survive to advanced age, although they die more prematurely than non-Tg mice, after 22 to 24 months.

TDP-43 (WT) (Petrucelli)

  • Absent
  • Absent
  • Observed
  • Observed
  • No Data
  • Absent
  • Observed
  • Observed
  • Observed

Not observed.

Neuronal loss was not detected in spinal cords of homozygous mice as assessed by TUNEL staining and caspase-3 staining.

Cytoplasmic eosinophilic aggregates in spinal motor neurons by one month of age in homozygous mice.

Astrogliosis and microgliosis in the anterior horn of the spinal cord by one month of age.

Unknown.

Atrophy of the gastrocnemius muscle was not observed.

By day 21, homozygous mice displayed body tremors and mild gait impairment which progressed into a “swimming gait” and severe motor impairment.

Homozygotes diverge early from non-Tg littermates in terms of body weight, showing significantly reduced weight gain.

 

Homozygous mice were sacrificed at one to two months of age when they were unable to right themselves.

TDP-43 (Wt-TAR6/6)

  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • Observed
  • Observed
  • Observed
  • Observed

Approximate 15 percent loss of layer V neurons in motor cortex at 6 months.

Spinal motor neuron loss observed at 3 months, with approximately 10 percent fewer anterior horn neurons in lumbosacral regions at 6 months, compared with non-transgenic mice.

Inclusions containing phosphorylated TDP-43 rarely observed in the nuclei and cytoplasm of spinal neurons.

Microgliosis in cortex and spinal cord prominent at 6 months; astrogliosis in cortex and spinal cord apparent at 1.5 months.

No data.

Muscle wasting, particularly in flanks.

Progressive motor impairment; abnormal hind limb reflexes observed as early as 1.5 months.

TAR6/6 mice had lower body weights than non-transgenic mice between 3.25 and 3.75 months age, but the two genotypes were similar at younger and older ages (at least until 4.25 months).

Average survival is 6.7 months.

ΔNLS-FUS

  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed

By 1 year, there was neuronal loss in the motor cortex.

Not observed at 1 year in the L5 anterior horn.

Ubiquitin- and p62-positive ΔNLS-FUS inclusions in motor cortex neurons.  

Microgliosis and astrocytosis were observed in the motor cortex.

No data.

No data.

Progressive motor impairments by 12 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as decreased performance on the Rotarod and hanging wire tests.

Decreased by 48 weeks.

Approximately 50% mortality by 60 weeks of age.

ΔNLS-FUS x TDP-43(WT)

  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed

By 1 year, there was neuronal loss in the motor cortex.

Not observed at 1 year in the L5 anterior horn.

Ubiquitin- and p62-positive ΔNLS-FUS inclusions in motor cortex neurons.  

Microgliosis and astrocytosis were observed in the motor cortex.

No data.

No data.

Progressive motor impairments by 8 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as decreased performance on the Rotarod and hanging wire test.

Decreased by 48 weeks.

Approximately 40% mortality by 60 weeks of age.

  • Sex-specific differences
  • Cortical Neuron Loss
  • Lower Motor Neuron Loss
  • Cytoplasmic Inclusions
  • Gliosis
  • NMJ Abnormalities
  • Muscle Atrophy
  • Motor Impairment
  • Body Weight
  • Premature Death

AAV-GFP-(GA)50

Observed

At 6 months, neuron loss observed in cortex, including layer V of motor cortex.

No Data

No data.

Observed

Neuronal poly(GA)- and ubiquitin-positive inclusions already present at 4-6 weeks; rare TDP-43-positive inclusions.

Observed

Astrogliosis, but not microgliosis, in cortex and hippocampus, seen at 6 months.

No Data

No data.

No Data

No data.

Observed

Deficits in tail-suspension and rotarod tests, seen at 6 months.

Observed

Decreased body weight in males, but not females, seen at 6 months.

No Data

No data.

AAV-GFP–(GR)100

Observed

Fewer cortical neurons than controls, observed as early as 6 weeks of age.

Absent

Not observed up to 6 months of age.

Observed

Very rare TDP-43 inclusions, observed at 6 months.

Observed

Astrogliosis and microgliosis in cortex and hippocampus, observed at 6 weeks.

No Data

No data.

No Data

No data.

Observed

Progressive motor deficits, seen in open-field, rotarod, rod-walk, and wire-hang tests.

Absent

Normal at 6 months of age.

No Data

No data.

C9-BAC500 (Brown)

Absent

Not observed.

Absent

Not observed.

Observed

No cytoplasmic mislocalization, or aggregation of TDP-43 in the motor cortex. However, dipeptide repeats accumulated at advanced age and formed small perinuclear inclusion bodies positive for poly-GP.

Absent

No signs of increased activation of microglia or astrocytes in the brain or spinal cord.

Absent

No difference in denervation of neuromuscular junctions at 24 months of age. No difference in motor or sensory spinal nerve root axon number or morphology.

No Data

Muscle histology has not been reported, but no overt muscle atrophy was observed.

Absent

No overt motor deficit as measured by the Rotarod and grip strength.

Absent

Non-significant trend for male C9BAC mice to be heavier than non-Tg controls. Female data have not yet been reported.

Absent

Normal lifespan beyond 2 years in male mice. Female data have not yet been reported.

C9-BACexp (Baloh/Lutz)

Absent

Not observed.

Absent

Not observed.

Observed

RNA foci throughout the nervous system starting at 3 months of age. Foci comprised of RNA transcripts in both the sense and antisense directions. Age-associated formation of dipeptide aggregates, e.g., poly-GP.

Absent

No increase in GFAP staining in the brain and spinal cord compared with non-Tg controls, even at 18 months of age.

Absent

Not observed.

Absent

Not observed.

Absent

No abnormalities in grip strength, Rotarod performance, or open-field testing at a young age (3 months) or advanced age (18 months), compared with non-Tg controls.

Absent

No abnormalities in body weight at a young age (3 months) or advanced age (18 months) compared with non-Tg controls.

Absent

Normal lifespan.

C9orf72 Knock-out

Absent

Not observed.

Absent

Not observed.

Absent

Not observed.

Absent

Not observed.

Absent

Not observed.

Absent

Not observed.

Observed

Reduced activity on open-field test. No abnormalities in grip strength or Rotarod performance.

Absent

Not observed.

Absent

Not observed.

C9ORF72(AAV)(G4C2)149

Observed

Cortical neuron loss by 6 months.

No Data

No data.

Observed

Cytoplasmic inclusions containing dipeptide repeat proteins (DPRs) derived from sense RNA seen in the cortex, hippocampus, cerebellum, and spinal cord; inclusions containing DPRs produced from antisense transcripts seen in the cortex and occasionally in the hippocampus.

Observed

Astrogliosis in the cortex by 3 months.

No Data

No data.

No Data

No data.

Observed

Deficits in the hanging wire test emerge between 3 and 6 months.

No Data

No data.

No Data

No data.

C9ORF72(AAV)(G4C2)66

Observed

Compared with mice expressing 2-repeats, the 66-repeat mice had 17 percent fewer neurons in the cortex at 6 months of age and 11 percent fewer Purkinje cells in the cerebellum. At this age neurons in the hippocampus and thalamus were not affected.

Absent

At 6 months, neuronal loss in the spinal cord was not detected.

Observed

By 6 months, inclusions of C9RAN dipeptides were present in neurons of the cortex and hippocampus, and to a lesser extent in the cerebellum and spinal cord. Inclusions contained polyGA, polyGP, and polyGR dipeptides and were largely ubiquitin-positive.

Observed

Astrogliosis in the cortex by 6 months.

No Data

No data.

No Data

No data.

Observed

At 6 months, 66-repeat mice perform as well as 2-repeat mice on the Rotarod on the first day of testing. However, they fail to improve during subsequent trials, suggesting impairments in coordination and/or motor learning.

Observed

At 6 months females had a lower body weight than mice expressing 2-repeats. Body weight did not differ in males.

No Data

No data.

CamKII;(GR)80

Observed

Neuron loss in the cortex, beginning between 3 and 6 months of age.

No Data

No data, but note that the transgene is not expressed in these neurons.

Absent

No TDP-43 inclusions seen in mice studied up to 8 months of age.

Observed

Microgliosis and astrogliosis evident at 6 and 9 months, respectively.

No Data

No data.

No Data

No data.

Absent

No difference between CamKII;(GR)80 mice and CamKII-tTA control mice up to 9 months of age.

Absent

No difference between CamKII;(GR)80 mice and CamKII-tTA control mice up to 11 months of age.

No Data

No data.

Endogenous Sod1 D83G

Observed

Neuronal numbers comparable to wild-type at 15 weeks, but about 20 percent loss of upper motor neurons by 29 weeks. Neurons in layer V of the motor cortex appeared selectively vulnerable.

Observed

Neuronal numbers comparable to wild-type at 6 weeks, but loss occurred by 15 weeks. The neuronal loss then stabilized; it was not more severe at 52 weeks of age.

Absent

Not observed.

Observed

Gliosis, of both astrocytes and microglia, was evident in the spinal cord by 15 weeks. It was further elevated at 52 weeks.

Observed

Denervation of a hindlimb muscle, the extensor digitorum longus, was detected by 52 weeks of age, and a decreased number of motor units in the EDL muscle.

No Data

Muscle atrophy was not reported, although changes to the muscle composition and histochemistry were observed.

Observed

Both male and female mice develop a variety of progressive motor symptoms. Grip strength was reduced at 6 weeks of age. Tremors developed by about 5 months of age. Rotarod performance was impaired, at 23 weeks in females and 67 weeks in males.

Observed

Homozygous mice, both male and female, showed reduced body weight by 4 weeks of age in contrast to wild-type littermates. Loss of excessive body weight was the primary factor leading to euthanasia.

Observed

Males reach end-stage sooner than females (495 ± 22 versus 588 ± 24 days). Animals were sacrificed when weight loss exceeded 20 percent of maximum weight, in accordance with animal-use guidelines. This is likely explained by the development of hepatocellular carcinomas due to SOD1 loss of function.

FUS-R521C

Absent

No detectable loss of cortical neurons; however, neurons in the sensorimotor cortex show reduced dendritic complexity and reduced synaptic density.

Observed

No detectable difference in spinal motor neurons at P0. At P16, about 20% loss of ChAT-positive neurons in the anterior horn of cervical spinal cord. At P30-P60, about 50% loss of anterior horn neurons. Remaining motor neurons show reduced dendritic complexity and synaptic density.

Observed

Less than 10% of spinal motor neurons have cytoplasmic FUS inclusions.

Observed

Prominent increase in microgliosis and astrogliosis in the anterior horn of the spinal cord by end stage.

Observed

Reduced innervation of neuromuscular junctions in the diaphragm.

Observed

The majority of mice have severe skeletal muscle atrophy in the hindlimb by end stage.

Observed

Early postnatal motor impairment, including abnormal hindlimb clasping when lifted by the tail, gait abnormalities, and impaired Rotarod performance.

Observed

Early postnatal growth is retarded, and the mice experience progressive loss of body weight.

Observed

The majority of mice in the N1F1 generation reached end stage and were sacrificed by postnatal day 100. Mice in subsequent generations live longer: about 40% reach end stage by postnatal day 200.

FUSDelta14 Knock-in

No Data

No data.

Observed

No lower motor neuron loss at 3 months but 14% reduction in the number of motor neurons in lumbar spinal cord at 12 months and 20% reduction by 18 months.

Absent

No increase in the number of spinal motor neurons that contain p62- or ubiquitin-positive inclusions in aged FUSDelta14 mice compared with aged wild-type mice.

No Data

No data.

Observed

Reduction in the number of intact neuromuscular junctions (fully innervated endplates) in hindlimb lumbrical muscles by 18 months of age.

No Data

No data.

Observed

Normal motor activity at 3 months of age but impaired hindlimb function by 15 months.

No Data

No data.

Observed

Reduced survival starting at 19 months of age.

FUSΔ14 (FUSd14)

Absent

Not observed.

Absent

Not observed.

Observed

Neuronal cytoplasmic inclusions were present by 3 months of age in the cerebral cortex. Inclusions occurred in about 20% of neurons and often co-labeled with ubiquitin.

Absent

No obvious astrogliosis or microglial activation at 3 months of age in the cerebral cortex.

No Data

No data.

No Data

No data.

Absent

When the mice were sacrificed at 3 months of age, they appeared healthy and displayed no obvious motor phenotype.

No Data

No data.

No Data

No data.

FusΔNLS

No Data

No data.

Observed

Approximately 30% reduction of motor neuron numbers in the dorsal spinal cord.

Observed

Ubiquitin pathology was observed in motor neurons, but p62 inclusions were not.

Observed

Slight increase in oligodendrocytes in the spinal cord white matter.

Observed

Fibrillation and fasciculation potentials were observed in the gastrocnemius or tibialis anterior muscles. There was also a reduction in compound muscle action potential amplitude.

No Data

No data.

Observed

By 10 months, mice demonstrated irregular walking patterns and reduced hang time on the inverted grid test. No deficits in grip strength or rotarod performance. Paralysis was not observed.

Absent

By 22 months, no weight loss was observed.

Absent

Life span was not altered.

hFUS (+/+) (PrP-hFUS)

Absent

In the brain, overt neuronal loss was absent at end stage (~11 weeks).

Observed

By end stage (~11 weeks), homozygous mice had lost about 60 percent of α-motor neurons in the anterior horn of the lumbar spinal cord.

Observed

By end stage, cytoplasmic FUS inclusions, described as “granular” and “globular,” develop in the spinal cord of homozygous mice. Ubiquitin-positive inclusions also develop, but do not co-localize with FUS inclusions. Neurons in the brain also develop “granular” and “skein-like” FUS inclusions.

Observed

By end stage (~11 weeks), homozygous mice had microgliosis and astrogliosis in the anterior horn of the spinal cord and in the white matter of the dorsal columns. Reactive gliosis was absent in the brain, despite cytoplasmic inclusions of FUS in some neurons.

Observed

Homozygous mice had about 20 percent fewer functional motor units in the extensor digitorum longus muscle as estimated by neurophysiological assessment.

Observed

Muscle histology from end stage (~11 weeks) homozygous mice showed focal muscle atrophy in hindlimb muscles.

Observed

Homozygous mice exhibited motor symptoms at four weeks of age, starting with a tremor and mild signs of hindlimb dysfunction, including gait abnormalities. Motor symptoms progressed quickly, ultimately developing into hindlimb paralysis.

Observed

Homozygous mice fail to gain weight normally starting about four weeks of age. Their body weight declines in subsequent weeks, often precipitating euthanasia.

Observed

Homozygous mice were euthanized between 10 and 13 weeks of age when they developed severe motor impairment or lost 25 percent of their body weight. Average survival was 82 ± 12 days.

hFUS-P525L

No Data

No data.

Observed

Progressive loss of motor neurons at lumbar level 5.

Absent

No FUS inclusions were observed.

Observed

Astrocytosis and microgliosis were observed in the spinal cord.

Observed

Progressive denervation of hindlimb muscles. Decreased density of synaptic vesicles and mitochondria with normal morphologies. Altered electrophysiological properties.

Observed

Reduced fiber diameter in the tibialis anterior muscle.

Observed

Deficits in wire hang test at 360 days.

No Data

No data.

Absent

Not observed by 360 days.

hFUS-R521C

No Data

No data.

Observed

Progressive loss of motor neurons at lumbar level 5.

Absent

No FUS inclusions were observed.

Observed

Astrocytosis and microgliosis were observed in the spinal cord.

Observed

Progressive denervation of hind limb muscles. 

No Data

No data.

No Data

No data.

No Data

No data.

Absent

Not observed by 360 days.

hPFN1-G118V

Observed

At 202 days, there was a decrease in the number of corticospinal neurons of the motor cortex.

Observed

Progressive loss of ventral horn neurons from 165 through 202 days of age.

Observed

Spinal cord motor neurons had TDP-43 puncta.

Observed

Astrocytosis and microgliosis were observed in the spinal cord at end stage.

Observed

Denervation of gastrocnemius muscle at end stage. Muscle action potential also had reduced amplitude.

Observed

At 165 days, hind limb muscle atrophy was observed.

Observed

Progressive motor impairments began ~ 120 days. Mice demonstrated tremors, limb clasping, muscle weakness, gait abnormalities, as well as reduced locomotion and decreased performance on the Rotarod. 

Observed

Body weight peaked ~ 150 days and then progressively decreased.

Observed

Mice were sacrificed at an average of 202 days when they were unable to right themselves. Females on average reached 191 days while males attained 213 days.

hTDP-43ΔNLS

Observed

Severe neuronal degeneration in the dentate gyrus and deep layers of the neocortex. Other regions, such as the hippocampal CA1 subfield and olfactory bulb, were relatively resistant to neurodegeneration. Approximately 50 percent of dentate gyrus neurons were lost one month after the transgene was activated.

Absent

Not observed.

Absent

High levels of cytosolic TDP-43 but only very rare aggregates (observed in less than 1 percent of cortical neurons and even rarer in other brain regions, such as the hippocampus and striatum).

Observed

Severe astrogliosis and microgliosis in areas affected by neurodegeneration, including cortical and hippocampal regions, as well as the corticospinal tract.

No Data

Unknown.

Absent

Not observed.

Observed

Spastic motor impairment indicated by an abnormal clasping response as early as one week after transgene induction. A variety of motor deficits develop by one month after transgene induction, including impaired coordination on the Rotarod and decreased grip strength.

No Data

Unknown.

Absent

Not observed.

NEFH-tTA x hTDP-43ΔNLS

Observed

Decreased cortical thickness indicative of neuronal degeneration beginning at four weeks off dox. By end stage, rNLS8 mice had significantly smaller brains than non-Tg littermates.

Observed

rNLS8 lost motor neurons in the lumbar spinal cord by six weeks off dox.

Observed

Cytoplasmic inclusions of TDP-43 occur as early as one week off dox in neurons in the brain. Inclusions accumulate over time and are present in many brain regions, including the motor cortex. TDP-43 inclusions are relatively rare in the spinal cord. Ubiquitin-positive inclusions are also seen.

Observed

Astrogliosis develops in many brain regions, including layer V of the motor cortex.

Observed

Denervation of the hindlimb muscle tibialis anterior was detectable by four weeks off dox, that is, two weeks prior to detectable loss of lower motor neurons.

Observed

At end-stage, rNLS8 mice exhibit gross muscle atrophy of the hindlimb muscles tibialis anterior and gastrocnemius.

Observed

rNLS8 mice develop a variety of motor impairments, starting with a deficit in hindlimb clasping and a fine tremor in the forelimb and/or hindlimb. They also develop progressive loss of grip strength (as measured by the wire-hang test) and a progressive decline in coordinated movement and balance (as measured by the accelerating Rotarod).

Observed

Body mass peaked at approximately 7 weeks of age (i.e., two weeks off dox) and then progressively dropped. Excessive loss of body weight (>30% decrease from peak weight) often defined end-stage.

Observed

rNLS8 mice die prematurely. They reach end-stage 8-18 weeks off dox, with a median survival of 10.3 weeks off dox.

PFN1-C71G

Absent

No neuronal loss in the cortex but neurodegeneration in medulla.

Observed

By 4 months there was a loss of cervical motor neurons and an increase in degenerating axons.

Observed

Cytoplasmic inclusions of PFN1, ubiquitin, and p62 in motor neurons around 6 months.

Observed

Microgliosis and astrogliosis observed in the dorsal horn by 5 months.

Observed

Denervation of gastrocnemius muscle occurs by 5 months.

Observed

Muscle atrophy in lower hind limb occurs by 6 months.

Observed

By 4 months, mice began showing minor gate changes and at 5-6 months they began demonstrating progressive deficits in Rotorod performance, vertical behaviors, and grip strength. 

Observed

Body weight peaked at 4-6 months and then progressively decreased.

Observed

Mice were sacrificed when they were incapable of locomotion following the paralysis of two or more limbs which occurred around 7 months of age.

PrP-hFUS (R495X)

Absent

Not observed.

Absent

Not observed.

Absent

Despite high levels of cytoplasmic FUS, neuronal inclusions were not observed.

No Data

No data.

Observed

A number of abnormalities were detected in the hindlimb musculature by electromyography (EMG). These phenotypes were detectable by 8-12 months of age and included fibrillation potentials, muscle denervation, and a reduction in the number of motor units.

No Data

No data.

Absent

Not observed.

No Data

No data.

Observed

Hemizygous mice sporadically developed intestinal swelling leading to premature death (mean survival 118 days). Homozygous mice were more severely affected (50 percent of the original cohort died around 59 days of age).

PrP-hFUS (WT)

No Data

No data.

No Data

No data.

Absent

Not observed.

No Data

No data.

Absent

Not observed.

No Data

No data.

Absent

Not observed.

No Data

No data.

Observed

Hemizygous mice die prematurely following a brief illness characterized by poor feeding. Mean survival of hemizygotes ~203 days.

SOD1 (G37R)

Absent

Upper motor neuron loss was not observed, although vacuolization occurred in brainstem neurons.

Observed

Motor neurons in the spinal cord and brainstem degenerated with overt neuronal loss in the ventral horn in some regions of the spinal cord by 19 weeks. The degenerative process involved extensive vacuolization.

Absent

Not observed.

Observed

Astrogliosis occurs in the spinal cord by 11 weeks of age, becoming more severe with age.

Observed

Denervated endplates have been observed.

Observed

Loss of motor axons, denervated endplates, atrophy of muscle fibers, and fiber type grouping observed by end-stage.

Observed

Motor impairment at 4-6 months, beginning with reduced spontaneous movement, then tremors, limb weakness, and poor grooming. Eventual paralysis of the hindlimbs.

Observed

Loss of body weight is observed.

Observed

Mice survive about 6 to 8 months.

SOD1-G85R (hybrid)

No Data

Unknown.

Observed

Extensive degeneration of large spinal axons coincident with the onset of clinical symptoms. By end stage, motor neurons in the ventral horn are lost.

Observed

Astrocytic inclusions occur early, about 6 months of age. The inclusions are immunoreactive for SOD1 and ubiquitin.

Observed

Astrogliosis and microgliosis are observed in the spinal cord starting around 6.5 months of age, and become more severe with age.

Observed

Denervation of muscle fibers is observed.

Observed

Hemizygous mice develop muscle weakness around 9 months of age, coincident with atrophy and denervation of muscle fibers.

Observed

Progressive motor impairment generally starting around 8 months with reduced grip strength in one hindlimb, rapidly spreading to other limbs and leading to paralysis within about two weeks.

Observed

Hemizygous mice start to lose weight at about 9 months of age.

Observed

End stage is characterized by paralysis at about 10 months of age.

SOD1-G93A (hybrid) (G1H)

Observed

Although outright upper motor neuron loss is absent or rare, degenerative signs (e.g., swollen neurites, Gallyas-positive aggregates, vacuoles, and neuritic spheroids) have been shown in motor regions of the cerebral cortex by five months of age.

Observed

Up to 50% loss of motor neurons in the cervical and lumbar segments of the spinal cord at end stage.

Observed

Inclusions accumulate in spinal motor neurons starting around 82 days of age. Inclusions generally take the form of spheroids or Lewy-body-like inclusions and commonly include a variety of neuronal intermediate filament proteins. TDP-43-positive inclusions are not present.

Observed

Gliosis, including the proliferation of reactive microglia and astrocytes, develops in parallel with motor neuron degeneration in the spinal cord.

Observed

Neuromuscular junctions degenerate around 47 days of age; fast-fatiguable motor neurons are affected first.

Observed

Longitudinal MRI has shown reduced muscle volume as early as 8 weeks of age. Atrophy is progressive. Skeletal muscle is affected, including limb and diaphragm.

Observed

Signs of motor impairment begin at about 3 months of age with a shaking tremor that leads to paralysis.

Observed

One of the first signs of illness is a slowing of growth and a plateauing of weight.

Observed

G1H mice reach end-stage disease by 5 months of age. Females typically survive longer than males.

TARDBP (A315T) (congenic)

No Data

These mice lose corticospinal tract axons, but outright loss of cortical neurons has not been reported in the model. When crossed with a Thy-1YFP model to label layer 5 pyramidal neurons, mice expressing TDP-43 (A315T) had fewer neurons at 15 weeks of age than YFP littermate controls (Zhang et al., 2016).

Absent

Most studies reported no lower motor neuron loss. One study observed 20% loss of large ventral horn neurons, possibly dependent on diet and how long the mice live in an individual colony.

Observed

Ubiquitinated inclusions in the cytoplasm of spinal motor neurons and cortical layer V neurons. No evidence for cytoplasmic TDP-43 inclusions.

Observed

Reports of astrocytosis in cortical layer 5 and in the spinal cord, as well as microgliosis in the spinal cord.

Observed

Denervation of neuromuscular junctions at end stage (~11% on normal diet; ~20% loss on a gel diet).

Observed

Atrophy of gastrocnemius muscle (gel diet).

Observed

Deficits have been reported in nonspecific measures of strength and coordination such as the Rotarod (males and females) and hanging-wire test (males). A severely impaired gait (“swimming gait”) was observed in mice fed a gel diet.

Observed

Weight loss is a consistent feature. Potentially confounded by severe gut phenotype.

Observed

Survival is limited by severe gastrointestinal dysfunction and can be prolonged with a gel diet. Lifespan varies, but in general on a standard diet males live about 3 months and females about 6 months.

TARDBP (A315T) (hybrid)

Observed

By end-stage, neuronal numbers in layer 5 of the motor cortex are decreased with about 50 percent loss of corticospinal tract axons.

Observed

By end-stage, ~20% loss of motor neurons in the L3-L5 region of the spinal cord.

Observed

By end-stage, cytoplasmic inclusions of ubiquitinated proteins in layer 5 neurons of motor, sensory, and cingulate cortex. Ubiquitin aggregates in ventral horn neurons. TDP-43 inclusions were rare.

Observed

By end-stage, selective increase in GFAP immunoreactivity in cortical layer 5.

No Data

Unknown.

Observed

By end-stage, atrophic muscle fibers were observed.

Observed

Gait abnormalities around three months of age, developing into a characteristic “swimming gait” by four to five months.

Observed

Weight was comparable to non-Tg mice at birth. By 4.5 months transgenic mice began to lose weight.

Observed

Survival for about 5 months (154 ± 19 days) before dying spontaneously or being euthanized. It was not reported if this analysis includes males, females, or both.

Tardbp Q331K Knock-In

No Data

No data.

No Data

No data.

No Data

No data.

No Data

No data.

No Data

No data.

No Data

No data.

No Data

No data.

No Data

No data.

No Data

No data.

Tardp LCDmut

No Data

No data.

Observed

28 percent reduction in the number of motor neurons in the sciatic motor neuron pool, compared with non-transgenic littermates.

Observed

At 18 months of age, p62- and ubiquitin-positive inclusions are found in the ventral regions of the spinal cord, although these inclusions do not appear to be located in the cytoplasm of motor neurons.

No Data

No data.

Observed

By 24 months, a 15 percent reduction in motor units innervating the extensor digitorum muscle.

No Data

No data.

Observed

Grip strength in both male and female mice begins to decline at 12 months of age. By 24 months, there is a nearly 40 percent reduction in force measured in tibialis anterior muscles.

No Data

No data.

Absent

Do not exhibit premature death, at least until 24 months of age.

Tardp_RRM2mut

No Data

No data.

Absent

Not observed at 2 years.

Absent

Not observed at 2 years.

No Data

No data.

Absent

Not observed at 2 years.

No Data

No data.

Absent

Not observed at 2 years.

No Data

No data.

Absent

Homozygous mutation is embryonic lethal.

TDP-43 (A315T)

Absent

Not observed.

Absent

Not observed.

Observed

Cytoplasmic accumulation of TDP-43 was observed by 10 months of age in the spinal cord. Furthermore, cytoplasmic aggregates were observed and often co-localized with ubiquitin. These inclusions are not detected at three months of age.

Observed

Progressive gliosis of both astrocytes and microglia, starting at a young age (by 3 months) in the brain and spinal cord.

No Data

Unknown.

No Data

Unknown.

Observed

At 38 weeks of age, mice develop impairments on the accelerating Rotarod relative to non-Tg littermates.

No Data

Unknown.

Absent

Not observed.

TDP-43 (A315T) (line 23)

Absent

Not observed.

Absent

Not observed.

Observed

Ubiquitin-positive cytoplasmic inclusions in neurons of the ventral horn and brainstem. Cytoplasmic aggregates of TDP-43 are largely absent, although rare phospho-TDP-43 inclusions were observed, especially at end-stage.

Observed

Mice exhibiting muscle weakness had astrocytosis in the ventral horn of the spinal cord.

No Data

Unknown.

Observed

Atrophy of muscle fibers in the quadriceps muscle of weak mice observed by day 44.

Observed

Progressive motor impairment, characterized by weakness, a decline in grip strength, and reduction in stride length. Weakness was usually more pronounced in the hindlimbs.

Observed

Progressive weight loss.

Observed

Line 23 mice survived about 2.5 months, mean survival 75 days. It was not reported whether this survival analysis includes males, females or both. Colony at Jackson Labs has longer mean survival.

TDP-43 (G348C)

Absent

Not observed.

Absent

Not observed.

Observed

Cytoplasmic accumulation of TDP-43 was observed by 10 months in the spinal cord. Cytoplasmic aggregates occurred and often co-localized with ubiquitin. These inclusions are not detected at 3 months of age.

Observed

Progressive gliosis of both astrocytes and microglia, starting at a young age (by 3 months) in the brain and spinal cord.

Observed

In 10-month-old mice, approximately 10% of NMJs in the gastrocnemius muscle were denervated, with another 20% partially denervated.

No Data

Unknown.

Observed

Performance on the Rotarod was comparable to non-Tg littermates until 36 weeks of age, and became progressively worse with age.

No Data

Unknown.

Absent

Normal lifespan.

TDP-43 (M337V)

Absent

Not observed.

Absent

Not observed.

Observed

TDP-43 protein was largely nuclear, although some cytoplasmic TDP-43 was also observed. Some mild cytoplasmic inclusions were reported.

Observed

Reactive astrocytes and activated microglia proliferate in the spinal cord and brainstem.

No Data

No data.

No Data

No data.

Observed

Body tremors apparent by day 21 and the mice had difficulty recruiting their hindlimbs, leading to an irregular gait pattern, described as “dragging.”

 

Observed

By one month of age, homozygotes have reduced body weight compared to non-Tg littermates.

 

Observed

70% mortality of homozygotes by around one month of age.

TDP-43 (M337V) (Mt-TAR6/6)

Observed

Severe neuronal loss in all CA regions of the hippocampus of homozygous mice. Neuronal loss was also observed in layer V cortical neurons and thalamic neurons.

Observed

Neuronal loss was observed in the spinal cords of homozygous mice.

Observed

Some homozygous mice developed cytoplasmic inclusions in layer V cortical neurons. These were often, but not always, ubiquitin–positive. They were not universally observed, even in end-stage mice.

Observed

Elevated astrogliosis and microgliosis compared with non-Tg controls, especially in the motor cortex and spinal cord. Gliosis in the hippocampus was seen at end stage.

No Data

Unknown.

No Data

Unknown.

Observed

Motor impairment developed quickly, by 11 days of age in homozygous mice, starting with an abnormal clasping reflex. They also develop a hunched posture, muscle twitches, and reduced mobility. Paralysis developed within days, leading to death. Hemizygotes do not develop motor symptoms until about one year of age, and impairment varied from mouse to mouse.

Observed

Early postnatal growth retardation in homozygous mice. By day 17 their average body weight is about half that of non-Tg controls.

Observed

Homozygous mice survived an average of just 17 days. In contrast, hemizygous Mt-TAR6 mice lived up to 24 months (average survival ~16.4 months).

TDP-43 (Q331K)

No Data

Unknown.

Observed

Age-dependent loss of lower motor neurons in the lumbar spinal cord. Loss is detectable as early as 2 months of age and is more pronounced by 10 months.

Absent

TDP-43 in the brain and spinal cord was predominantly nuclear. Cytoplasmic TDP-43 aggregates were absent.

Observed

Elevated astrogliosis and microgliosis in the ventral horn of spinal cord by 10-12 months of age compared with non-Tg controls.

Observed

Reduction in neuromuscular junction endplates by 10-12 months of age. Remaining NMJs often had a “bleb-like” appearance.

No Data

Muscle fiber abnormalities including centralized nuclei and damage by 10-12 months of age.

Observed

Tremor, abnormal hindlimb clasping, impaired performance on the Rotarod were detectable starting around 3 months of age. Reduced grip strength occurred later.

No Data

Unknown.

No Data

Unknown.

TDP-43 (Q331K) Knock-In (Line 52)

Observed

25% loss of parvalbumin-positive neurons at 5 months.

Absent

Not observed.

Absent

Not observed.

No Data

Unknown.

Absent

Not observed.

No Data

Unknown.

Absent

Not observed.

Observed

Increased body weight.

Observed

Mutation may be deleterious to male embryos.

TDP-43 (WT) (Elliott)

Absent

Not observed.

Absent

Not observed.

Observed

Cytoplasmic ubiquitin-positive inclusions in skeletal muscle cells. Some TDP-43 inclusions, too.

No Data

No data.

No Data

No data.

Observed

An analysis of the quadriceps muscle, showed signs of myopathy, including variable muscle fiber size and disorganization of the muscle architecture.

Observed

Progressive motor impairment starting with external rotation of one hind limb followed by bilateral weakness and low muscle tone. Variable penetrance of this phenotype.

Observed

Progressive weight loss.

Observed

The mean survival of hemizygous mice was 109 days (it is not clear if this value represents males, females, or both).

TDP-43 (WT) (Julien model)

Absent

Not observed.

Absent

Not observed.

Absent

Primarily nuclear localization of human TDP-43.

Observed

Gliosis, both microgliosis and astrogliosis, occur early in the brain and spinal cord. Reactive glia were detected as early as 3 months of age, with more by 10 months.

Observed

Some NMJ denervation was observed by 10 months of age. About 5% of NMJs at the gastrocnemius muscle were denervated, with another 20 percent partially denervated.

No Data

No data.

Observed

Decreased performance on the accelerating Rotarod at 42 weeks of age. Further impairment at 52 weeks.

No Data

No data.

No Data

No data.

TDP-43 (WT) (Kumar-Singh)

Observed

In homozygous mice, quantitative loss of neurons occurs in the motor cortex compared with non-Tg littermates. Both superficial and deep cortical layers of the anterior cortex are affected.

Observed

By day 18, homozygous mice exhibited about 25 percent loss of motor neurons in the lumbar spinal cord compared with non-Tg littermates.

Observed

Homozygous mice developed cytoplasmic inclusions in the brain and spinal cord, many of which were ubiquitin-positive. A minority of inclusions co-labeled with TDP-43. Ultrastructural analysis revealed ubiquitin–negative cytoplasmic inclusions in anterior horn neurons to be abnormal accumulations of mitochondria.

Observed

Astrogliosis and microgliois especially in cortical layer V of the anterior cortex, including motor and somatosensory cortex, and in the spinal cord.

No Data

No data.

No Data

No data.

Observed

Homozygous mice exhibit an abnormal clasping reflex by postnatal day 14. Other early motor deficits include a shortened stride, a wide stance, and frequent stumbling. By day 18, reduced performance on the Rotarod. Complete paralysis occurs ~10 days after onset.

Observed

Size and weight of homozygous mice lag behind hemizygotes and non-Tg littermates.

Observed

Homozygous mice survive an average of just 24 days. In contrast, hemizygous mice survive to advanced age, although they die more prematurely than non-Tg mice, after 22 to 24 months.

TDP-43 (WT) (Petrucelli)

Absent

Not observed.

Absent

Neuronal loss was not detected in spinal cords of homozygous mice as assessed by TUNEL staining and caspase-3 staining.

Observed

Cytoplasmic eosinophilic aggregates in spinal motor neurons by one month of age in homozygous mice.

Observed

Astrogliosis and microgliosis in the anterior horn of the spinal cord by one month of age.

No Data

Unknown.

Absent

Atrophy of the gastrocnemius muscle was not observed.

Observed

By day 21, homozygous mice displayed body tremors and mild gait impairment which progressed into a “swimming gait” and severe motor impairment.

Observed

Homozygotes diverge early from non-Tg littermates in terms of body weight, showing significantly reduced weight gain.

 

Observed

Homozygous mice were sacrificed at one to two months of age when they were unable to right themselves.

TDP-43 (Wt-TAR6/6)

Observed

Approximate 15 percent loss of layer V neurons in motor cortex at 6 months.

Observed

Spinal motor neuron loss observed at 3 months, with approximately 10 percent fewer anterior horn neurons in lumbosacral regions at 6 months, compared with non-transgenic mice.

Observed

Inclusions containing phosphorylated TDP-43 rarely observed in the nuclei and cytoplasm of spinal neurons.

Observed

Microgliosis in cortex and spinal cord prominent at 6 months; astrogliosis in cortex and spinal cord apparent at 1.5 months.

No Data

No data.

Observed

Muscle wasting, particularly in flanks.

Observed

Progressive motor impairment; abnormal hind limb reflexes observed as early as 1.5 months.

Observed

TAR6/6 mice had lower body weights than non-transgenic mice between 3.25 and 3.75 months age, but the two genotypes were similar at younger and older ages (at least until 4.25 months).

Observed

Average survival is 6.7 months.

ΔNLS-FUS

Observed

By 1 year, there was neuronal loss in the motor cortex.

Absent

Not observed at 1 year in the L5 anterior horn.

Observed

Ubiquitin- and p62-positive ΔNLS-FUS inclusions in motor cortex neurons.  

Observed

Microgliosis and astrocytosis were observed in the motor cortex.

No Data

No data.

No Data

No data.

Observed

Progressive motor impairments by 12 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as decreased performance on the Rotarod and hanging wire tests.

Observed

Decreased by 48 weeks.

Observed

Approximately 50% mortality by 60 weeks of age.

ΔNLS-FUS x TDP-43(WT)

Observed

By 1 year, there was neuronal loss in the motor cortex.

Absent

Not observed at 1 year in the L5 anterior horn.

Observed

Ubiquitin- and p62-positive ΔNLS-FUS inclusions in motor cortex neurons.  

Observed

Microgliosis and astrocytosis were observed in the motor cortex.

No Data

No data.

No Data

No data.

Observed

Progressive motor impairments by 8 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as decreased performance on the Rotarod and hanging wire test.

Observed

Decreased by 48 weeks.

Observed

Approximately 40% mortality by 60 weeks of age.