Species: Mouse
Genes: FUS, TARDBP
Mutations: FUS ΔNLS
Modification: FUS: Transgenic; TARDBP: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis
Strain Name: N/A
This mouse model of ALS is a cross between the ΔNLS-FUS line, which overexpresses human FUS lacking the nuclear localization signal (NLS), and the TDP-43(WT) line, which overexpresses wild-type human TDP-43 (Shiihashi et al., 2016). Both lines utilize a Thy1 promoter.
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Cortical Neuron Loss
By 1 year, there was neuronal loss in the motor cortex.
Lower Motor Neuron Loss
Not observed at 1 year in the L5 anterior horn.
Cytoplasmic Inclusions
Ubiquitin- and p62-positive ΔNLS-FUS inclusions in motor cortex neurons.
Gliosis
Microgliosis and astrocytosis were observed in the motor cortex.
Motor Impairment
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.
Premature Death
Approximately 40% mortality by 60 weeks of age.
Last Updated: 14 Apr 2017
Further Reading
No Available Further Reading
Species: Mouse
Genes: FUS
Mutations: FUS ΔNLS
Modification: FUS: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis
Strain Name: N/A
FUS (Fused in Sarcoma) is a member of a family of RNA-binding proteins with roles in transcription, RNA processing, RNA transport, and translation. Mutations in FUS, many of which are clustered near the nuclear localization signal (NLS) at the C-terminus, are linked to familial cases of ALS. Additionally, truncation and frameshift mutations can result in the deletion of the NLS.
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Cortical Neuron Loss
By 1 year, there was neuronal loss in the motor cortex.
Lower Motor Neuron Loss
Not observed at 1 year in the L5 anterior horn.
Cytoplasmic Inclusions
Ubiquitin- and p62-positive ΔNLS-FUS inclusions in motor cortex neurons.
Gliosis
Microgliosis and astrocytosis were observed in the motor cortex.
Motor Impairment
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.
Premature Death
Approximately 50% mortality by 60 weeks of age.
Last Updated: 14 Apr 2017
Further Reading
No Available Further Reading
Species: Mouse
Genes: FUS
Mutations: FUS R521C
Modification: FUS: Knock-In
Disease Relevance: Amyotrophic Lateral Sclerosis
Strain Name: N/A
Summary
FUS (Fused in Sarcoma) is a member of a family of RNA-binding proteins with roles in transcription, RNA processing, RNA transport, and translation. Mutations in FUS, including R521C, are linked to rare familial cases of ALS.
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Lower Motor Neuron Loss
Progressive loss of motor neurons at lumbar level 5.
Cytoplasmic Inclusions
No FUS inclusions were observed.
Gliosis
Astrocytosis and microgliosis were observed in the spinal cord.
NMJ Abnormalities
Progressive denervation of hind limb muscles.
Premature Death
Not observed by 360 days.
Last Updated: 17 Mar 2017
Further Reading
No Available Further Reading
Species: Mouse
Genes: FUS
Mutations: FUS P525L
Modification: FUS: Knock-In
Disease Relevance: Amyotrophic Lateral Sclerosis
Strain Name: N/A
Summary
FUS (Fused in Sarcoma) is a member of a family of RNA-binding proteins with roles in transcription, RNA processing, RNA transport, and translation. Mutations in FUS, many of which are clustered near the nuclear localization signal at the C-terminus, are linked to familial cases of ALS. The P525L mutation in FUS is associated with a rare and aggressive form of juvenile-onset ALS.
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Lower Motor Neuron Loss
Progressive loss of motor neurons at lumbar level 5.
Cytoplasmic Inclusions
No FUS inclusions were observed.
Gliosis
Astrocytosis and microgliosis were observed in the spinal cord.
NMJ Abnormalities
Progressive denervation of hindlimb muscles. Decreased density of synaptic vesicles and mitochondria with normal morphologies. Altered electrophysiological properties.
Muscle Atrophy
Reduced fiber diameter in the tibialis anterior muscle.
Motor Impairment
Deficits in wire hang test at 360 days.
Premature Death
Not observed by 360 days.
Last Updated: 17 Mar 2017
Further Reading
No Available Further Reading
Species: Mouse
Genes: LRRK2
Mutations: LRRK2 G2019S
Modification: LRRK2: Transgenic
Disease Relevance: Parkinson's Disease
Strain Name: B6;C3-Tg(PDGFB-LRRK2*G2019S)340Djmo/J
Summary
These transgenic mice overexpress mutant human LRRK2 throughout the brain via a promoter that drives neuronal-specific expression (Ramonet et al., 2011). Nonetheless, the mutant human protein is also overexpressed in the lung and spleen (Kozina et al., 2018).
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Neuronal Loss
By 19-21 months, mice lose 18 percent of TH-positive dopaminergic neurons in the substantia nigra pars compacta and 14 percent of dopaminergic dendrites in the substantia nigra pars reticulata. At 1-2 months neuronal numbers were normal. Some authors do not see differences in TH staining up to 2 years of age. No abnormal neuronal loss is observed in the ventral tegmental area or cerebellum.
Dopamine Deficiency
At 14-15 months of age, hemizygous mice had normal levels of striatal dopamine, DOPAC, and HVA. However, in the olfactory bulb, levels of HVA and DOPAC were lower, but dopamine was unchanged.
α-synuclein Inclusions
Around 2 years of age, mice did not exhibit abnormalities in α-synuclein in the ventral midbrain, striatum, or cerebral cortex. However, one study found α-synuclein accumulation in whole brain lysates of 12- to 19-month-old transgenic mice.
Neuroinflammation
Around 2 years of age, mice did not have GFAP abnormalities in the ventral midbrain, striatum, or cerebral cortex. However, activated microglia were reported in the striatum at 14 months, and CD68 and TNF-α levels were increased in whole brains at 4-6 months. Others have not observed differences in Iba-1 staining (microglial marker) at 6, 12, or 18 months in the striatum or substantia nigra.
Mitochondrial Abnormalities
Increased numbers and condensation of mitochondria in striatal microglia were reported at 14 months. Abnormally high levels of condensed mitochondria were also observed in cortical and striatal neurons at 17-18 months.
Motor Impairment
Rotarod performance deteriorated in 14- to 18-month-old mice, but minor deficits are already observed as early as 8 months of age. Muscle weakness observed on the hanging wire test by 8 months of age. No change in pre-pulse inhibition of the acoustic startle reflex.
Non-Motor Impairment
Anxiety/depression-like symptoms were observed at 10-12 months of age.
Last Updated: 21 Dec 2023
Further Reading
No Available Further Reading
Species: Mouse
Genes: Park2
Mutations: Parkin Q311X
Modification: Park2: Transgenic
Disease Relevance: Parkinson's Disease
Strain Name: FVB/NJ-Tg(Slc6a3-PARK2*Q311X)AXwy/J
Summary
The Q311X mutation is a nonsense mutation that produces a C-terminally truncated parkin, just 155 amino acids long. Parkin-Q311X mice (line A) have two copies of the transgene (Tg) integrated in tandem in a bacterial artificial chromosome (BAC), although its integration site is unknown. Notably, as hemizygous mice age, they lose dopaminergic neurons and develop progressive changes in motor behavior, including lower activity levels (Lu et al., 2009).
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Neuronal Loss
Progressive loss of dopaminergic neurons in the substantia nigra, starting as early as 6 months of age. About 40 percent loss by 16 months of age with a corresponding decrease in dopaminergic projections to the striatum. Neurons in the ventral tegmental area were relatively spared.
Dopamine Deficiency
Surviving nigral neurons at 16 months of age had reduced tyrosine hydroxylase expression. By 19-21 months, striatal concentrations of dopamine and the dopamine metabolite DOPAC were decreased compared with non-Tg littermates.
α-synuclein Inclusions
Lewy body-like inclusions were not observed at any age, however, mutant mice exhibit age-dependent accumulation of proteinase-K resistant endogenous α-synuclein in the substantia nigra at 16 months of age.
Mitochondrial Abnormalities
Mitochondrial dysfunction observed as early as 1 month of age, based on electron microscopy (e.g., lacking an outer membrane, swollen) and expression of the short isoform of OPA1.
Motor Impairment
Behavior was fairly normal at 3 months, but motor abnormalities were detected by 16 months of age, including hypoactivity and deficits in coordination and in motor response to sensory stimuli.
Non-Motor Impairment
Autophagy and lysosomal dysfunction in mutant mice at 16-17 months of age.
Last Updated: 18 Jun 2024
Further Reading
No Available Further Reading
Species: Mouse
Genes: PINK1
Mutations: Pink1 G309D
Modification: PINK1: Knock-In
Disease Relevance: Parkinson's Disease
Strain Name: B6;129-Pink1tm1Aub/J
Summary
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Neuronal Loss
Neuronal loss was not observed at 18 months of age (total neuronal population and TH-positive subset).
Dopamine Deficiency
Decreased dopamine concentration in the striatum by 9 months of age.
α-synuclein Inclusions
No Lewy body-like inclusions or α-synuclein aggregates in the brainstem or substantia nigra, but expression levels of α-synuclein are altered in brainstem/midbrain.
Neuroinflammation
Expression of factors involved in Toll-like receptor signaling were increased in the cerebellum, as were astrocytic and microglial markers in the corticospinal tract and striatum at 18 months.
Mitochondrial Abnormalities
By 3 months of age the mice exhibited a mitochondrial import defect. This phenotype was more severe at 6 months and import was reduced nearly 50% by 12 months of age. By 6 months, ATP production, respiration, and mitochondrial membrane potential were also reduced.
Motor Impairment
At 16 months of age Pink1-/- mice exhibited decreased spontaneous locomotor activity. Strength and coordination were intact.
Non-Motor Impairment
Mutant mice performed similarly to wild-type mice in tests assessing the startle reflex, sweating, and anxiety.
Last Updated: 03 Jul 2024
Further Reading
No Available Further Reading
Species: Mouse
Genes: LRRK2
Modification: LRRK2: Transgenic
Disease Relevance: Parkinson's Disease
Strain Name: FVB/N-Tg(LRRK2)1Cjli/J
Summary
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Neuronal Loss
No data on neuron numbers are available, but neurite length is reduced in primary hippocampal neurons and primary nigral tyrosine hydroxylase-positive neurons of WT-OX mice versus non-Tg mice.
Dopamine Deficiency
Striatal dopamine levels, as measured by PET imaging with [18F]FDOPA uptake, are higher in WT-OX versus non-Tg mice.
α-synuclein Inclusions
No in vivo data, but α-syn colocalization with LAMP-2 is increased in cultured neurons from WT-OX mice.
Mitochondrial Abnormalities
Mitochondrial morphology and levels of proteins involved in mitochondrial fission (Drp1 and Fis1) are normal at 12 months of age.
Motor Impairment
WT-OX mice (12 months) are hyperactive on several parameters of the open-field test. Gait analysis (Cat-Walk system) was also perturbed relative to non-Tg controls. However, the number of rears did not differ.
Last Updated: 16 Feb 2024
Further Reading
No Available Further Reading
Species: Mouse
Genes: LRRK2
Mutations: LRRK2 G2019S
Modification: LRRK2: Transgenic
Disease Relevance: Parkinson's Disease
Strain Name: B6.Cg-Tg(Lrrk2*G2019S)2Yue/J
Summary
This transgenic (Tg) mouse overexpresses a mutant form of Lrrk2 (G2019S) using a bacterial artificial chromosome (BAC) (Li et al., 2010). Transgene expression is driven by the mouse Lrrk2 promoter sequence. Hemizygous mice develop an age-associated decrease in striatal dopamine, but no loss of dopaminergic neurons or behavioral motor deficits.
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Neuronal Loss
No evidence of neuronal or other cell death in any brain region, including the cortex, striatum, and hippocampus. There was no difference in the number of dopaminergic neurons in the substantia nigra compared to littermate controls at 6 or 12 months.
Dopamine Deficiency
Age-related decline in striatal dopamine content. Levels were decreased at 12 months of age, but not significantly different from controls at 6 months of age. Also, decreased dopamine metabolite homovanillic acid (HVA).
α-synuclein Inclusions
No evidence of α-synuclein inclusions up to 18 months of age. However, there is mixed evidence on whether cultured mutant hippocampal neurons have increased levels of α-synuclein protein. After exposure to exogenous α-synuclein fibrils, mutant neurons developed more α-synuclein inclusions than non-Tg neurons.
Neuroinflammation
Application of α-synuclein fibrils leads to exacerbated responses (more inclusions and greater infiltration of pro-inflammatory monocytes).
Mitochondrial Abnormalities
Primary cultured cells from Tg mice exhibit mitochondrial fragmentation and membrane depolarization.
Motor Impairment
Behavior in hemizygous mice was comparable to littermate controls in terms of activity levels (open-field test) and coordination (beam-walk test) at 6 and 12 months, , but not at 18 months of age, when Tg mice develop motor deficits (Rotarod).
Non-Motor Impairment
Tg mice spend less time in the REM sleep phase at 12 and 18 months of age. Age-dependent increase in plasma corticosterone (present starting at 6-8 months of age). Nuclear envelope integrity is perturbed in dopaminergic neurons at 12 months.
Last Updated: 08 Nov 2023
Further Reading
No Available Further Reading
Species: Mouse
Genes: Pink1
Modification: Pink1: Knock-Out
Disease Relevance: Parkinson's Disease
Strain Name: B6.129S4-Pink1tm1Shn/J
Summary
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Neuronal Loss
No decrease in the number of dopaminergic neurons in the substantia nigra at 2-3 months or 8-9 months of age. Neuronal morphology also grossly intact.
Dopamine Deficiency
Overall striatal levels of dopamine did not significantly differ from levels in wild-type mice at 2-3 months or 8-9 months of age.
Mitochondrial Abnormalities
Altered shape, density, and movement of dendritic mitochondria observed in cultured primary neurons from embryonic mice. Also, an abnormal rise in serum cytokines in response to acute mitochondrial stress was reported in vivo. By 2 months of age, mitochondrial dysfunction observed in cardiomyocytes.
Motor Impairment
Reduced spontaneous locomotor activity and skill reported at 3-6 months.
Non-Motor Impairment
Modest vocalization deficits observed at 4-6 months. Reduced BDNF levels in the midbrain and cortex at 10 months. Cardiac hypertrophy observed at 2 and 6 months of age.
Last Updated: 20 Apr 2024
Further Reading
No Available Further Reading
Benjamin Wolozin 
June Kinoshita 
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