title: Resistance of alpha -synuclein null mice to the parkinsonian neurotoxin MPTP.
abstract: Parkinson's disease (PD) is most commonly a sporadic illness, and is characterized by degeneration of substantia nigra dopamine (DA) neurons and abnormal cytoplasmic aggregates of alpha-synuclein. Rarely, PD may be caused by missense mutations in alpha-synuclein. MPTP, a neurotoxin that inhibits mitochondrial complex I, is a prototype for an environmental cause of PD because it produces a pattern of DA neurodegeneration that closely resembles the neuropathology of PD. Here we show that alpha-synuclein null mice display striking resistance to MPTP-induced degeneration of DA neurons and DA release, and this resistance appears to result from an inability of the toxin to inhibit complex I. Contrary to predictions from in vitro data, this resistance is not due to abnormalities of the DA transporter, which appears to function normally in alpha-synuclein null mice. Our results suggest that some genetic and environmental factors that increase susceptibility to PD may interact with a common molecular pathway, and represent the first demonstration that normal alpha-synuclein function may be important to DA neuron viability.
authors.affiliation: Department of Neurology, Columbia University, New York, NY 10027, USA. wtd3@columbia.edu
authors.forename: William
authors.initials: W
authors.lastname: Dauer
authors.forename: Nikolai
authors.initials: N
authors.lastname: Kholodilov
authors.forename: Miquel
authors.initials: M
authors.lastname: Vila
authors.forename: Anne-Cecile
authors.initials: AC
authors.lastname: Trillat
authors.forename: Rose
authors.initials: R
authors.lastname: Goodchild
authors.forename: Kristin E
authors.initials: KE
authors.lastname: Larsen
authors.forename: Roland
authors.initials: R
authors.lastname: Staal
authors.forename: Kim
authors.initials: K
authors.lastname: Tieu
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schmitz
authors.forename: Chao Annie
authors.initials: CA
authors.lastname: Yuan
authors.forename: Marcelo
authors.initials: M
authors.lastname: Rocha
authors.forename: Vernice
authors.initials: V
authors.lastname: Jackson-Lewis
authors.forename: Steven
authors.initials: S
authors.lastname: Hersch
authors.forename: David
authors.initials: D
authors.lastname: Sulzer
authors.forename: Serge
authors.initials: S
authors.lastname: Przedborski
authors.forename: Robert
authors.initials: R
authors.lastname: Burke
authors.forename: Rene
authors.initials: R
authors.lastname: Hen
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism / Q000494:pharmacology*; D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D002478:Cells, Cultured; D015259:Dopamine Agents / Q000378:metabolism / Q000494:pharmacology*; D004351:Drug Resistance; D042967:Electron Transport Complex I; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D010300:Parkinson Disease / Q000378:metabolism*; D051843:Synucleins; D051844:alpha-Synuclein
chemical_list: D015306:Biogenic Monoamines; D015259:Dopamine Agents; 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; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I; D015655:1-Methyl-4-phenylpyridinium