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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


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


Experimental neurology

Publication Data

May 15, 2002

Associated Grants

  • Agency: NIEHS NIH HHS, Id: ES01247
  • Agency: NIEHS NIH HHS, Id: ES05017
  • Agency: NIEHS NIH HHS, Id: ES05905
  • Agency: NINDS NIH HHS, Id: NS 19576
  • Agency: NINDS NIH HHS, Id: NS36420
  • Agency: NIEHS NIH HHS, Id: R01 ES09391

Mesh Terms

  • 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