Resistance of α-synuclein null mice to the parkinsonian neurotoxin MPTP

William Dauer, Nikolai Kholodilov, Miquel Vila, Anne Cecile Trillat, Rose Goodchild, Kristin E. Larsen, Roland Staal, Kim Tieu, Yvonne Schmitz, Chao Annie Yuan, Marcelo Rocha, Vernice Jackson-Lewis, Steven Hersch, David Sulzer, Serge Przedborski, Robert Burke, Rene Hen

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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 α-synuclein. Rarely, PD may be caused by missense mutations in α-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 α-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 α-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 α-synuclein function may be important to DA neuron viability.

Original languageEnglish (US)
Pages (from-to)14524-14529
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number22
DOIs
StatePublished - Oct 29 2002
Externally publishedYes

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    Dauer, W., Kholodilov, N., Vila, M., Trillat, A. C., Goodchild, R., Larsen, K. E., Staal, R., Tieu, K., Schmitz, Y., Yuan, C. A., Rocha, M., Jackson-Lewis, V., Hersch, S., Sulzer, D., Przedborski, S., Burke, R., & Hen, R. (2002). Resistance of α-synuclein null mice to the parkinsonian neurotoxin MPTP. Proceedings of the National Academy of Sciences of the United States of America, 99(22), 14524-14529. https://doi.org/10.1073/pnas.172514599