Resistance of alpha -synuclein null mice to the parkinsonian neurotoxin MPTP.
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.
Dauer
William
W
Department of Neurology, Columbia University, New York, NY 10027, USA. wtd3@columbia.edu
Kholodilov
Nikolai
N
Vila
Miquel
M
Trillat
Anne-Cecile
AC
Goodchild
Rose
R
Larsen
Kristin E
KE
Staal
Roland
R
Tieu
Kim
K
Schmitz
Yvonne
Y
Yuan
Chao Annie
CA
Rocha
Marcelo
M
Jackson-Lewis
Vernice
V
Hersch
Steven
S
Sulzer
David
D
Przedborski
Serge
S
Burke
Robert
R
Hen
Rene
R
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
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