Mutations: SNCA E46K
Modification: SNCA: Transgenic
Disease Relevance: Parkinson's Disease
Strain Name: NTac:SD-Tg(SNCA*E46K)70CJLi
Genetic Background: Sprague-Dawley
Availability: Available through Taconic Cat #10679; Cryopreserved.
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).
In this model human α-synuclein protein is expressed at levels two- to threefold above endogenous α -synuclein. Mutant protein is expressed throughout the brain.
There is no overt neuronal loss in hemizygous rats up to 12 months of age. Furthermore, quantification of the density of striatal dopamine terminals showed no differences between mutant and non-Tg rats. Although there was no overt loss of dopaminergic neurons, dopaminergic neurons in the substantia nigra exhibited higher levels of nitrotyrosine, suggesting greater oxidative stress.
By 12 months of age, hemizygous E46K rats accumulate significant α-synuclein in the brain. Diffuse staining was observed in the neuropil by immunohistochemistry. Intracellular aggregates occur in neurons; aggregates were noted to be smaller than is typically observed in the PD brain. Aggregates also occurred in dopaminergic neurons of the substantia nigra and the ventral tegmental area. In the striatum and cortex, accumulated α-synuclein protein appeared primarily in neuronal processes.
E46K rats did not exhibit a loss of dopamine in the striatum at 12 months of age. Likewise, striatal serotonin levels were unchanged. However, levels of two dopamine metabolites (dihydroxyphenylacetic acid and homovanillic acid) were reduced by approximately 25 percent. Transmitter turnover was decreased.
Behavioral assessment has not been reported. No overt changes in motor phenotype were observed up to 12 months of age.
Interestingly, E46K rats exhibit heightened sensitivity to low-dose rotenone. Rats at six months of age treated with rotenone (2.5 mg/kg/day) developed motor symptoms such as bradykinesia, postural instability, and rigidity more quickly than non-Tg rats on the same rotenone regimen. The combined genetic and pharmacological “hit” also potentiated loss of dopaminergic terminals but did not affect the number of dopaminergic neurons in the substantia nigra.
E46K rats are viable and fertile.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Dopamine Deficiency
- Motor Impairment
- Neuronal Loss
- Non-Motor Impairment
- Mitochondrial Abnormalities
No overt loss of dopaminergic neurons out to 12 months of age.
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.
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.
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
- Cannon JR, Geghman KD, Tapias V, Sew T, Dail MK, Li C, Greenamyre JT. Expression of human E46K-mutated α-synuclein in BAC-transgenic rats replicates early-stage Parkinson's disease features and enhances vulnerability to mitochondrial impairment. Exp Neurol. 2013 Feb;240:44-56. PubMed.
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