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Behavioral and Neurochemical Effects of Wild-Type and Mutated Human α-Synuclein in Transgenic Mice

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Abstract

Human α-synuclein (hα-SYN) is implicated in the Parkinson's disease phenotype (PDP) based on a variety of studies in man, animal models, and in vitro studies. The normal function of hα-SYN and the mechanism by which it contributes to the PDP remains unclear. We created transgenic mice expressing either wild-type (hwα-SYN) or a doubly mutated (hm2α-SYN) form of hα-SYN under control of the 9-kb rat tyrosine hydroxylase promoter. These mice expressed hα-SYN in cell bodies, axons, and terminals of the nigrostriatal system. The expression of hα-SYN in nigrostriatal terminals produced effects in both constructs resulting in increased density of the dopamine transporter and enhanced toxicity to the neurotoxin MPTP. Expression of hm2α-SYN reduced locomotor responses to repeated doses of amphetamine and blocked the development of sensitization. Adult hwα-SYN-5 transgenic mice had unremarkable dopaminergic axons and terminals, normal age-related measures on two motor coordination screens, and normal age-related measures of dopamine (DA) and its metabolites. Adult hm2α-SYN-39 transgenic mice had abnormal axons and terminals, age-related impairments in motor coordination, and age-related reductions in DA and its metabolites. Expression of hm2α-SYN adversely affects the integrity of dopaminergic terminals and leads to age-related declines in motor coordination and dopaminergic markers.

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