TY - JOUR
T1 - Resistance of α-synuclein null mice to the parkinsonian neurotoxin MPTP
AU - Dauer, William
AU - Kholodilov, Nikolai
AU - Vila, Miquel
AU - Trillat, Anne Cecile
AU - Goodchild, Rose
AU - Larsen, Kristin E.
AU - Staal, Roland
AU - Tieu, Kim
AU - Schmitz, Yvonne
AU - Yuan, Chao Annie
AU - Rocha, Marcelo
AU - Jackson-Lewis, Vernice
AU - Hersch, Steven
AU - Sulzer, David
AU - Przedborski, Serge
AU - Burke, Robert
AU - Hen, Rene
PY - 2002/10/29
Y1 - 2002/10/29
N2 - 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.
AB - 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.
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U2 - 10.1073/pnas.172514599
DO - 10.1073/pnas.172514599
M3 - Article
C2 - 12376616
AN - SCOPUS:0037195109
SN - 0027-8424
VL - 99
SP - 14524
EP - 14529
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 22
ER -