Abstract
Alpha-synuclein (aSyn) is the main component of Lewy bodies, the histopathological marker in Parkinson’s disease (PD), and point mutations and multiplications of the aSyn coding SNCA gene correlate with early onset PD. Therefore, various transgenic mouse models overexpressing native or point-mutated aSyn have been developed. Although these models show highly increased aSyn expression they rarely capture dopaminergic cell loss and show a behavioural phenotype only at old age, whereas SNCA mutations are risk factors for PD with earlier onset. The aim of our study was to re-characterize a transgenic mouse strain carrying both A30P and A53T mutated human aSyn. Our study revealed decreased locomotor activity for homozygous transgenic mice starting from 3 months of age which was different from previous studies with this mouse strain that had behavioural deficits starting only after 7–9 months. Additionally, we found a decreased amphetamine response in locomotor activity and decreased extracellular dopaminergic markers in the striatum and substantia nigra with significantly elevated levels of aSyn oligomers. In conclusion, homozygous transgenic A30P*A53T aSyn mice capture several phenotypes of PD with early onset and could be a useful tool for aSyn studies.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease with an annual incidence of 160 per 100 000 people over 65 years old[1]
Between 17:00 and 20:00 tg mice showed higher locomotor activity compared to wt littermates (Fig. 1B, genotype effect: F1,26 = 10.622, p = 0.003, repeated measures 2-way ANOVA). 9 months old tg mice had significantly lower activity between 12:00 and 14:00, and between 22:00 and 02:00 compared to wt littermates (Fig. 1C, 12:00–14:00 genotype effect: F1,28 = 9.725, p = 0.004; 22:00– 02:00 genotype effect: F1,28 = 19.213, p = 0.0001, repeated measures 2-way ANOVA), while between 18:00 and 20:00 tg mice were more active compared to wt littermates (Fig. 1C, genotype effect: F1,28 = 8.924, p = 0.006, repeated measures 2-way ANOVA)
Th effect was similar but more pronounced than the one seen in the 6 months old tg animals. 12 months old tg mice were more active compared to wt littermates during 18:00 and 20:00 period (Fig. 1D, genotype effect: F1,35 = 6.620, p = 0.014, repeated measures 2-way ANOVA)
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease with an annual incidence of 160 per 100 000 people over 65 years old[1]. Richfield et al.[20] introduced a mouse model expressing double mutated human aSyn gene with both A30P and A53T point mutations under the rat tyrosine hydroxylase (TH) promoter (C57BL/6J-Tg (TH-SNCA*A30P*A53T)39Eric/J) that combined two well-characterized familial site mutations of SNCA to model PD These tg mice expressed human aSyn in cell bodies, axons, and terminals in the nigrostriatal pathway, and had decreased locomotor activity at age 7–9 and 13–23 months, and lowered concentration of DA and its metabolites in the striatal tissue at age 16–18 months. Similar to several other aSyn tg mice, younger mice did not have significant changes in locomotor activity or in striatal DA concentration Both A30P and A53T familial point mutations in SNCA are a risk factor for early onset PD19 but these features were not captured in the earlier study. We found several behavioural and histological changes that were not described in the original publication
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