AAV-GFP-(GA)50 <p>-</p>, <p>GFP-(GA)<sub>50</sub></p>
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
AAV-GFP–(GR)100 <p>-</p>, <p>GFP–(GR)<sub>100</sub></p>
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
C9-BAC500 (Brown) <p>Brown</p>, <p>C9-BAC[GGGGCC]500</p>
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
C9-BACexp (Baloh/Lutz) 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 ; LiveO'Rourke et al., 2015 Yes
C9ORF72(AAV)(G4C2)149 <p>-</p>, <p>(G<sub>4</sub>C<sub>2</sub>)<sub>149</sub></p>, <p>149-repeat mice</p>
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
C9ORF72(AAV)(G4C2)66 <p>-</p>, <p>66-repeat mice</p>, <p>Petrucelli’s AAV C9 model</p>
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 Knock-out <p>-</p>, <p>C9orf72 KO</p>, <p>3110043O21Rik Knock-out</p>
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;(GR)80 <p>-</p>, <p>CamKII-tTA;(GR)<sub>80</sub> (line 16)</p>, <p>CamKII;(GR)<sub>80</sub></p>
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
Endogenous Sod1 D83G 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 ; CryopreservedJoyce et al., 2015 Yes
FUSΔ14 (FUSd14) 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
FUSDelta14 Knock-in 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
FusΔNLS <p>-</p>, <p>Fus-dNLS</p>, <p>Fus-deltaNLS</p>, <p>Fus-ΔNLS/+</p>
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
FUS-R521C 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 ; CryopreservedQiu et al., 2014 Yes
hFUS-P525L <p>-</p>, <p>Tau-ON-hFUS-P525L</p>
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
hFUS (+/+) (PrP-hFUS) <p>PrP-hFUS</p>
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 ; CryopreservedMitchell et al., 2012 Yes
hFUS-R521C <p>-</p>, <p>Tau-ON-hFUS-R512C</p>
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
hPFN1-G118V <p>-</p>, <p>PrP-PFN1-G118V</p>
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
hTDP-43ΔNLS 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 ; LiveIgaz et al., 2011 Yes
NEFH-tTA x hTDP-43ΔNLS <p>-</p>, <p>rNLS8</p>, <p>regulatable NLS</p>
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
ΔNLS-FUS <p>-</p>, <p>dNLS-FUS</p>, <p>deltaNLS-FUS</p>
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 TDP-43(WT) <p>-</p>, <p>ΔNLS-FUS x TARDBP</p>, <p>deltaNLS-FUS x TAR4</p>
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
PFN1-C71G <p>-</p>, <p>Thy1.2-PFN1<sup>C71G</sup>/Prp-PFN1<sup>C71G</sup></p>
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) 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
PrP-hFUS (WT) 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
SOD1 (G37R) 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 (hybrid) <p>-</p>, <p>SOD1 (G85R) (line 148)</p>
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
SOD1-G93A (hybrid) (G1H) <p>G1H</p>, <p>High-copy SOD1-G93A</p>, <p>B6SJL.SOD1-G93A</p>, <p>Tg(hSOD1-G93A)1GUR mice</p>, <p>Gurney mice</p>
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
TARDBP (A315T) (congenic) <p>-</p>, <p>Prp-TDP43<sup>A315T</sup></p>
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 ; LiveWegorzewska et al., 2009 , Hatzipetros et al., 2014 Yes
TARDBP (A315T) (hybrid) <p>-</p>, <p>Baloh’s TDP-43</p>, <p>C57BL/6-CBA TDP-43 A315T</p>
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
Tardbp Q331K Knock-In 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
Tardp LCDmut <p>-</p>, <p>LCDmut</p>
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
Tardp_RRM2mut <p>-</p>, <p>RRM2mut</p>
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
TDP-43 (A315T) 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
TDP-43 (A315T) (line 23) 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 ; CryopreservedStallings et al., 2010 Yes
TDP-43 (G348C) 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) <p>-</p>, <p>TDP-43 M337V PrP (line 4)</p>
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 ; CryopreservedXu et al., 2011 Yes
TDP-43 (M337V) (Mt-TAR6/6) 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
TDP-43 (Q331K) 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-43 (Q331K) Knock-In (Line 52) <p>-</p>, <p>TDP-43<sup>Q331K</sup> KI (Line 52)</p>
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
TDP-43 (WT) (Elliott) <p>Elliott</p>, <p>WT TDP-43 (line 4)</p>
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
TDP-43 (WT) (Julien model) <p>Julien model</p>, <p>Wild-type TDP-43</p>
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
TDP-43 (WT) (Kumar-Singh) <p>-</p>, <p>WT-TAR4/4</p>, <p>WT-TAR4</p>
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
TDP-43 (WT) (Petrucelli) <p>-</p>, <p>Wild-type TDP-43 transgenic (line 3C)</p>, <p>TDP-43<sub>PrP</sub></p>
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 ; CryopreservedXu et al., 2010 Yes
TDP-43 (Wt-TAR6/6) <p>-</p>, <p>WT-TAR6/6</p>, <p>TAR6/6</p>
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
