Bennett M Catherine
Blanchette Rockefeller Neurosciences Institute, Rockville, MD, USA.
Pharmacol Ther. 2005 Mar;105(3):311-31. doi: 10.1016/j.pharmthera.2004.10.010. Epub 2004 Dec 8.
Alpha-synuclein is a 140 amino acid neuronal protein that has been associated with several neurodegenerative diseases. A point mutation in the gene coding for the alpha-synuclein protein was the first discovery linking this protein to a rare familial form of Parkinson's disease (PD). Subsequently, other mutations in the alpha-synuclein gene have been identified in familial PD. The aggregated proteinaceous inclusions called Lewy bodies found in PD and cortical Lewy body dementia (LBD) were discovered to be predominantly alpha-synuclein. Aberrant aggregation of alpha-synuclein has been detected in an increasing number of neurodegenerative diseases, collectively known as synucleopathies. Alpha-synuclein exists physiologically in both soluble and membrane-bound states, in unstructured and alpha-helical conformations, respectively. The physiological function of alpha-synuclein appears to require its translocation between these subcellular compartments and interconversion between the 2 conformations. Abnormal processing of alpha-synuclein is predicted to lead to pathological changes in its binding properties and function. In this review, genetic and environmental risk factors for alpha-synuclein pathology are described. Various mechanisms for in vitro and in vivo alpha-synuclein aggregation and neurotoxicity are summarized, and their relevance to neuropathology is explored.
α-突触核蛋白是一种由140个氨基酸组成的神经元蛋白，与多种神经退行性疾病相关。编码α-突触核蛋白的基因中的一个点突变是首次将该蛋白与一种罕见的家族性帕金森病（PD）联系起来的发现。随后，在家族性PD中又鉴定出了α-突触核蛋白基因的其他突变。在PD和皮质路易体痴呆（LBD）中发现的称为路易小体的聚集性蛋白质内含物主要是α-突触核蛋白。在越来越多的神经退行性疾病中都检测到了α-突触核蛋白的异常聚集，这些疾病统称为突触核蛋白病。α-突触核蛋白在生理状态下分别以可溶性和膜结合状态存在，其构象分别为无结构和α-螺旋构象。α-突触核蛋白的生理功能似乎需要其在这些亚细胞区室之间转运以及在两种构象之间相互转换。预计α-突触核蛋白的异常加工会导致其结合特性和功能发生病理变化。在这篇综述中，描述了α-突触核蛋白病理的遗传和环境危险因素。总结了体外和体内α-突触核蛋白聚集及神经毒性的各种机制，并探讨了它们与神经病理学的相关性。
