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PMID: 12376616 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Resistance of alpha -synuclein null mice to the parkinsonian neurotoxin MPTP.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 99 ·No. 22 ·2002-10-29 ·Pages 14524-9

Dauer W, Kholodilov N, Vila M, Trillat AC, Goodchild R, Larsen KE, Staal R, Tieu K, Schmitz Y, Yuan CA, Rocha M, Jackson-Lewis V, Hersch S, Sulzer D, Przedborski S, Burke R, Hen R

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.

MeSH Terms
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/metabolism,pharmacology 1-Methyl-4-phenylpyridinium/metabolism Animals Biogenic Monoamines/metabolism Cells, Cultured Dopamine Agents/metabolism,pharmacology Drug Resistance Electron Transport Complex I Female Humans Male Mice Mice, Knockout NADH, NADPH Oxidoreductases/metabolism Nerve Tissue Proteins/genetics,metabolism Neurons/cytology,drug effects Parkinson Disease/metabolism Synucleins alpha-Synuclein
Chemicals
Biogenic Monoamines Dopamine Agents Nerve Tissue Proteins SNCA protein, human Snca protein, mouse Synucleins alpha-Synuclein 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine NADH, NADPH Oxidoreductases Electron Transport Complex I 1-Methyl-4-phenylpyridinium
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Dauer William
Department of Neurology, Columbia University, New York, NY 10027, USA. [email protected]
Kholodilov Nikolai
Vila Miquel
Trillat Anne-Cecile
Goodchild Rose
Larsen Kristin E
Staal Roland
Tieu Kim
Schmitz Yvonne
Yuan Chao Annie
Rocha Marcelo
Jackson-Lewis Vernice
Hersch Steven
Sulzer David
Przedborski Serge
Burke Robert
Hen Rene
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.172514599
Email
[email protected]
Published
2002-10-29
Epub
2002-00-10
Pages
14524-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC137916
Subset
IM
Corrections
CommentIn
PMID: 12391311
External Links
PubMed source DOI: 10.1073/pnas.172514599 PMC Full Text View journal details
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