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.
Richfield
Eric K
EK
Department of Pathology and Lab Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642, USA.
Thiruchelvam
Mona J
MJ
Cory-Slechta
Deborah A
DA
Wuertzer
Charles
C
Gainetdinov
Raul R
RR
Caron
Marc G
MG
Di Monte
Donato A
DA
Federoff
Howard J
HJ
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000375:Aging; D000661:Amphetamine; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004298:Dopamine / Q000172:deficiency / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D020022:Genetic Predisposition to Disease; D006801:Humans; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced; D017729:Presynaptic Terminals / Q000473:pathology; D011401:Promoter Regions, Genetic; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051843:Synucleins; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics; D051844:alpha-Synuclein
D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine