Moszczynska Anna, Saleh Jumana, Zhang Hongyu, Vukusic Brian, Lee Frank J S, Liu Fang
Department of Neuroscience, Centre for Addiction and Mental Health, Clarke Division, 250 College Street, Toronto, ON M5T 1R8, Canada.
J Mol Neurosci. 2007;32(3):217-27. doi: 10.1007/s12031-007-0037-0.
Parkinson's disease is characterized by progressive neuronal degeneration of dopaminergic neurons in the substantia nigra. Many factors are thought to contribute to the neuronal cell death that occurs in Parkinson's disease, including alpha-synuclein-mediated toxicity. Previously, we have reported that alpha-synuclein directly couples to the carboxyl tail of the dopamine transporter (DAT) and that the alpha-synuclein/DAT protein complex formation accelerates DAT-mediated cellular dopamine (DA) uptake and DA-induced cellular apoptosis. In the present study, we report that parkin, an E2-dependent E3 protein ubiquitin ligase associated with recessive early onset Parkinson's disease, exerts a protective effect against DA-induced alpha-synuclein-dependent cell toxicity. Parkin impairs the alpha-synuclein/DAT coupling by interacting with the carboxyl-terminus of the DAT and blocks the alpha-synuclein-induced enhancement in both DAT cell surface expression and DAT-mediated DA uptake. Moreover, we have found that parkin protects against DA-induced cell toxicity in dopaminergic SK-N-SH cells. These findings will help identify the role of these proteins in the etiology and/or maintenance of Parkinson's disease.
帕金森病的特征是黑质中多巴胺能神经元进行性神经变性。许多因素被认为与帕金森病中发生的神经元细胞死亡有关，包括α-突触核蛋白介导的毒性。此前，我们报道α-突触核蛋白直接与多巴胺转运体（DAT）的羧基末端结合，且α-突触核蛋白/DAT蛋白复合物的形成加速了DAT介导的细胞多巴胺（DA）摄取和DA诱导的细胞凋亡。在本研究中，我们报道了与隐性早发性帕金森病相关的E2依赖性E3蛋白泛素连接酶帕金（parkin）对DA诱导的α-突触核蛋白依赖性细胞毒性具有保护作用。帕金通过与DAT的羧基末端相互作用来削弱α-突触核蛋白/DAT的结合，并阻断α-突触核蛋白诱导的DAT细胞表面表达增强和DAT介导的DA摄取。此外，我们发现帕金可保护多巴胺能SK-N-SH细胞免受DA诱导的细胞毒性。这些发现将有助于确定这些蛋白质在帕金森病病因和/或维持中的作用。
