Dauer William, 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
Department of Neurology, Columbia University, New York, NY 10027, USA.
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14524-9. doi: 10.1073/pnas.172514599. Epub 2002 Oct 10.
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.
帕金森病（PD）通常是一种散发性疾病，其特征是黑质多巴胺（DA）神经元变性以及α-突触核蛋白在细胞质中异常聚集。极少数情况下，PD可能由α-突触核蛋白的错义突变引起。MPTP是一种抑制线粒体复合体I的神经毒素，是PD环境病因的一个典型例子，因为它会导致一种与PD神经病理学极为相似的DA神经变性模式。我们在此表明，α-突触核蛋白基因敲除小鼠对MPTP诱导的DA神经元变性和DA释放具有显著抗性，这种抗性似乎源于毒素无法抑制复合体I。与体外数据的预测相反，这种抗性并非由于DA转运体异常，DA转运体在α-突触核蛋白基因敲除小鼠中似乎功能正常。我们的结果表明，一些增加PD易感性的遗传和环境因素可能与一条共同的分子途径相互作用，并且首次证明正常的α-突触核蛋白功能可能对DA神经元的存活至关重要。
