Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice.
Human alpha-synuclein (halpha-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 halpha-SYN and the mechanism by which it contributes to the PDP remains unclear. We created transgenic mice expressing either wild-type (hwalpha-SYN) or a doubly mutated (hm2alpha-SYN) form of halpha-SYN under control of the 9-kb rat tyrosine hydroxylase promoter. These mice expressed halpha-SYN in cell bodies, axons, and terminals of the nigrostriatal system. The expression of halpha-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 hm2alpha-SYN reduced locomotor responses to repeated doses of amphetamine and blocked the development of sensitization. Adult hwalpha-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 hm2alpha-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 hm2alpha-SYN adversely affects the integrity of dopaminergic terminals and leads to age-related declines in motor coordination and dopaminergic markers.
Pubmed ID: 12009758 RIS Download
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine | Aging | Amphetamine | Animals | Behavior, Animal | Brain | Corpus Striatum | Disease Models, Animal | Disease Progression | Dopamine | Dopamine Plasma Membrane Transport Proteins | Genetic Predisposition to Disease | Humans | Membrane Glycoproteins | Membrane Transport Proteins | Mice | Mice, Transgenic | Motor Activity | Mutagenesis, Site-Directed | Nerve Tissue Proteins | Parkinson Disease | Parkinson Disease, Secondary | Presynaptic Terminals | Promoter Regions, Genetic | Substantia Nigra | Synucleins | Tyrosine 3-Monooxygenase | alpha-Synuclein