Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice.

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Richfield, EK; Thiruchelvam, MJ; Cory-Slechta, DA; Wuertzer, C; Gainetdinov, RR; Caron, MG; Di Monte, DA; Federoff, HJ

Published Date

  • May 2002

Published In

Volume / Issue

  • 175 / 1

Start / End Page

  • 35 - 48

PubMed ID

  • 12009758

International Standard Serial Number (ISSN)

  • 0014-4886

Digital Object Identifier (DOI)

  • 10.1006/exnr.2002.7882

Language

  • eng

Conference Location

  • United States