Species: Mouse
Genes: SNCA
Mutations: SNCA A53T
Modification: SNCA: Transgenic
Disease Relevance: Parkinson's Disease
Strain Name: B6.Cg-2310039L15RikTg(Prnp-SNCA*A53T)23Mkle/J. Formerly: B6.Cg-Tg(Prnp-SNCA*A53T)23Mkle/J
Summary
These transgenic mice overexpress human α-synuclein with a PD-associated mutation (A53T). Hemizygous mice overexpress mutant α-synuclein in the brain at levels about sixfold higher than endogenous mouse α-synuclein. They develop severe progressive motor impairments around one year of age, but no overt neuronal loss (Lee et al., 2002). The data on this page refer to phenotypes observed in hemizygous animals; homozygous mice from this strain are not viable.
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
Overt neuronal loss was not reported in these mice.
Dopamine Deficiency
In symptomatic mice, striatal dopamine and metabolites DOPAC and HVA are comparable to wildtype, but at 5 months, striatal tyrosine hydroxylase is reduced. Increased D1 receptors in the substantia nigra and decreased dopamine transporters in the nucleus accumbens and striatum have been reported.
α-synuclein Inclusions
Prior to motor deficits, these mice develop accumulations of α-synuclein in select neuronal populations, including the midbrain, cerebellum, brainstem, and spinal cord. The protein aggregates do not resemble Lewy bodies, but are thioflavin-S-positive, indicating fibrillar structure.
Neuroinflammation
In symptomatic mice, increased GFAP immunoreactivity was observed in select brain regions, including the dorsal midbrain, deep cerebellar nuclei, brainstem, and spinal cord. Cortex, hippocampus, and substantia nigra did not have increased reactivity compared with non-Tg controls.
Mitochondrial Abnormalities
At 11–14 months, mitochondria in brainstem neurons were enlarged and their co-localization with the mitochondrial fission protein Drp1 was reduced.
Motor Impairment
These mice develop severe motor impairment starting around 9-16 months of age. The deficits start out with mild hyperactivity at 7 months and progress to a wobbling movement, decreased activity, and ultimately paralysis and death.
Non-Motor Impairment
At 11–12 months, spatial memory was impaired as assessed by the Barnes circular maze.
Last Updated: 08 Feb 2019
Further Reading
No Available Further Reading
Species: Rat
Genes: SNCA
Mutations: SNCA E46K
Modification: SNCA: Transgenic
Disease Relevance: Parkinson's Disease
Strain Name: NTac:SD-Tg(SNCA*E46K)70CJLi
Summary
This rat model overexpresses mutant human α-synuclein carrying the E46K mutation associated with familial Parkinson’s disease. Hemizygous rats develop small α-synuclein aggregates in dopaminergic neurons, along with signs of oxidative stress. There is no overt loss of dopaminergic neurons. Behavioral characterization has not been reported (Cannon et al., 2013).
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 overt loss of dopaminergic neurons out to 12 months of age.
Dopamine Deficiency
No dopamine deficiency in the striatum at 12 months of age. No serotonin deficiency in the striatum. Dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid were reduced by approximately 25 percent and transmitter turnover was decreased.
α-synuclein Inclusions
By 12 months of age, intracellular aggregates were observed in dopaminergic neurons of the substantia nigra and ventral tegmental area. Aggregates noted to be fairly small compared to those observed in PD brain. In the striatum and cortex α -synuclein accumulation appeared primarily in neuronal processes.
Mitochondrial Abnormalities
Motor Impairment
No overt motor differences out to 12 months of age, unless challenged with low-dose rotenone, upon which the rats exhibit bradykinesia, postural instability, and rigidity.
Last Updated: 22 Mar 2017
Further Reading
No Available Further Reading
Species: Rat
Genes: Park7 (DJ1)
Modification: Park7 (DJ1): Knock-Out
Disease Relevance: Parkinson's Disease
Strain Name: LE-Park7em1sage; HsdSage:LE-Park7em1Sage; formerly LEH-Park7tm1sage
Summary
This knockout (KO) rat model was created at SAGE Labs (acquired first by Horizon Discovery, then by Envigo, and most recently by Inotiv) in collaboration with the Michael J. Fox Foundation. The rat carries a disrupted Park7 gene, which encodes the protein DJ-1. Homozygous DJ-1 KO rats develop motor (e.g., gait, strength) impairments and loss of dopaminergic neurons in the substantia nigra; however, levels of striatal dopamine are high (Dave et al., 2014).
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
Age-related decreases in TH-positive dopaminergic neurons were reported in the substantia nigra and locus coeruleus reaching approximately 50 percent by 8 months of age. No change was found in TH-immunoreactivity in the ventral tegmental area or striatum.
Dopamine Deficiency
Striatal dopamine level was increased 2-3 fold in KO rats compared to wild-type levels at 8 months of age. Dopaminergic innervation of the dorsal striatum was intact in DJ-1 KO rats at 4 and 6 months of age compared to wild-type rats. Basal levels of dopamine metabolites and evoked levels of dopamine in the striatum were not different between KO and wild-type rats.
α-synuclein Inclusions
Staining for α-synuclein revealed no increase in the striatum or in any other brain region assessed.
Mitochondrial Abnormalities
At 3 months of age, the mitochondrial proteome in DJ-1 KO rats was differentially expressed compared to wild-type rats. Mitochondrial respiration was also increased in KO versus wild-type rats
Motor Impairment
Abnormalities in gait and strength, vocalizations, and tongue movements were observed. By 4 months, the rats exhibited abnormal paw positioning and a shorter stride. Males showed impaired licking, longer and more frequent ultrasonic vocalizations, and an accelerated decrease in average call intensity with age. Fine motor skills were also impaired in KO versus wild-type rats by 7 months of age.
Non-Motor Impairment
Olfactory detection enhanced (16 mos). Short-term memory abnormal (4.5, 15 mos). Appetitive instrumental learning normal (4, 6, 8 mos). Coping behavior (forced-swim test) impaired (6 mos). No anxiety-like behavior (elevated plus maze; 4, 8, 17 mos), less anxiety on light-dark box (6, 8 mos). No sucrose preference at 9 mos. Sensorimotor function (adhesive removal) unaffected (4, 7, 13 mos).
Last Updated: 26 Sep 2023
Further Reading
No Available Further Reading
Species: Mouse
Genes: APP, PSEN1, MAPT
Mutations: PSEN1: deltaE9
Modification: APP: Transgenic; PSEN1: Transgenic; MAPT: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
To investigate the influence of human tau (hTau) on amyloid pathology, APPswe/PSEN1dE9 (APP/PS1) mice were crossed with the CaMKIIa-tTA and Tg21221 lines to create the APP/PS1/rTg21221 mouse. The transgene from the Tg21221 mouse encodes wild-type hTau with four microtubule binding domains and lacking amino terminal inserts (4R/0N) under control of a tetracycline responsive elements (TRE) promotor (Hoover et al., 2010).
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+.
Plaques
Cortical plaques observed between 8-10 months. Plaques larger than in control mice not expressing human tau.
Tangles
No tangles. Aggregates of misfolded and phosphorylated tau observed between 8-10 months.
Synaptic Loss
Decreased synapse density adjacent to plaques relative to more distal areas.
Neuronal Loss
Neuronal loss observed adjacent to plaques relative to more distal areas.
Gliosis
Increased astrocytosis adjacent to plaques relative to more distal areas.
Last Updated: 13 Apr 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: PFN1
Mutations: PFN1 G118V
Modification: PFN1: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis
Strain Name: N/A
Mutations in profilin, including G118V, are linked to rare familial cases of ALS. The profilin protein is best known for its role in polymerizing actin, but has also been shown to aggregate with RNA and proteins commonly associated with stress granules.
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
At 202 days, there was a decrease in the number of corticospinal neurons of the motor cortex.
Lower Motor Neuron Loss
Progressive loss of ventral horn neurons from 165 through 202 days of age.
Cytoplasmic Inclusions
Spinal cord motor neurons had TDP-43 puncta.
Gliosis
Astrocytosis and microgliosis were observed in the spinal cord at end stage.
NMJ Abnormalities
Denervation of gastrocnemius muscle at end stage. Muscle action potential also had reduced amplitude.
Muscle Atrophy
At 165 days, hind limb muscle atrophy was observed.
Motor Impairment
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
Body weight peaked ~ 150 days and then progressively decreased.
Premature Death
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.
Last Updated: 03 Mar 2017
Further Reading
No Available Further Reading
Species: Mouse
Genes: PFN1
Mutations: PFN1 C71G
Modification: PFN1: Multi-transgene
Disease Relevance: Amyotrophic Lateral Sclerosis
Strain Name: FVB/N-Tg(Prnp-PFN1*C71G)22Zxu Tg(Thy1-PFN1*C71G)67Zxu/J
Summary
Mutations in profilin, including C71G, are linked to rare familial cases of ALS. The profilin protein is best known for its role in polymerizing actin, but has also been shown to aggregate with RNA and proteins commonly associated with stress granules.
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
No neuronal loss in the cortex but neurodegeneration in medulla.
Lower Motor Neuron Loss
By 4 months there was a loss of cervical motor neurons and an increase in degenerating axons.
Cytoplasmic Inclusions
Cytoplasmic inclusions of PFN1, ubiquitin, and p62 in motor neurons around 6 months.
Gliosis
Microgliosis and astrogliosis observed in the dorsal horn by 5 months.
NMJ Abnormalities
Denervation of gastrocnemius muscle occurs by 5 months.
Muscle Atrophy
Muscle atrophy in lower hind limb occurs by 6 months.
Motor Impairment
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
Body weight peaked at 4-6 months and then progressively decreased.
Premature Death
Mice were sacrificed when they were incapable of locomotion following the paralysis of two or more limbs which occurred around 7 months of age.
Last Updated: 03 Mar 2017
Further Reading
No Available Further Reading
Species: Mouse
Genes: MAPT
Modification: MAPT: Knock-In
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy
Strain Name: N/A
In humans, the A152T MAPT mutation appears to act as a risk modifier to multiple neurodegenerative diseases including AD, FTD, and DLB. In contrast, the majority of pathogenic mutations in MAPT are causally linked to FTD. To investigate the consequences of the A152T mutation, this mouse model overexpresses the 2N4R isoform of human tau with the A152T mutation.
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+.
Tangles
Tangles in hippocampus, cortex, and spinal cord starting at 3 months with age-dependent increases. Hyperphosphorylation, conformation changes, and mislocalization.
Synaptic Loss
Synaptophysin, but not PSD95, decreased in hippocampus and cortex at 12 months. By Golgi staining, spines unchanged in CA1 at 10 months, increased in CA3 at 12 months, and decreased in CA1 and CA3 at 16 months.
Neuronal Loss
Neuron loss in the hippocampus and cortex at 12 months.
Gliosis
Astrocytosis and microgliosis at 10 months.
Cognitive Impairment
No change at 10 months but at 16 months deficits in learning and memory (Morris water maze).
Last Updated: 10 Feb 2017
Further Reading
No Available Further Reading
Species: Mouse
Genes: MAPT
Modification: MAPT: Transgenic
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy
Strain Name: C57BL/6-Tg(tetO-MAPT*A152T)L1Lms/J
In humans, the A152T MAPT mutation appears to act as a risk modifier to multiple neurodegenerative diseases, including AD, FTD, and DLB. In contrast, the majority of pathogenic mutations in MAPT are causally linked to FTD. To investigate the consequences of the A152T mutation, this mouse model overexpresses the 1N4R isoform of human tau with the A152T mutation.
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+.
Tangles
Abnormal accumulations of soluble tau were observed, but not tangles or tangle-like structures.
Neuronal Loss
Neuron loss in the hippocampus was observed by 20 months.
Gliosis
Astrocytosis, but no differences in microglia.
Cognitive Impairment
In the Morris water maze, performance was impaired after 17 months of age. Nest building was impaired at 10-14 months. Social interaction, anxiety, exploratory behavior, and motor functions were unaltered.
Last Updated: 30 Nov 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: MAPT
Modification: MAPT: Transgenic
Disease Relevance: Progressive Supranuclear Palsy, Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy
Strain Name: N/A
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+.
Tangles
Abnormally phosphorylated tau detected at two months and by eight months tau was mislocalized and misfolded and dystrophic neurites were observed. Tangle-like structures observed in the hippocampus by 14 months.
Synaptic Loss
At 14 months synapsin1 protein levels were decreased but synaptophysin levels remained at wild-type levels.
Neuronal Loss
Cell death was not formally assessed, however, overt neuronal death was not seen in the hippocampus.
Gliosis
Gliosis was not observed at 14 months.
Cognitive Impairment
In the Morris water maze, Tau35 had the same performance as wild-type animals at six months but developed progressive deficits by eight months.
Last Updated: 03 Feb 2017
Further Reading
No Available Further Reading
COMMENTS / QUESTIONS
Washington University
This paper rigorously demonstrates that overexpression of one mutant form of alpha-synuclein results in synuclein aggregation, inclusions, and neurological disease while overexpression of wild-type human synuclein and another mutant does not. These mice should be very useful for further studying the pathophysiology of alpha-synucleinopathies.
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