α-突触核蛋白的结构生物学研究

Structural Studies of α-Synuclein

α-突触核蛋白(α-synuclein, α-syn)聚集形成纤维状结构,进而形成路易小体(Lewy bodies, LBs)。LBs是帕金森病(Parkinson’s disease, PD)、多系统萎缩(multiple system atrophy, MSA)和路易小体痴呆(dementia with Lewy bodies, DLB)等神经退行性疾病的典型细胞病变特征,也是发病的一个关键环节。近年来,冷冻电镜技术的进步使解析高分辨率α-突触核蛋白原纤维结构成为可能。对α-突触核蛋白不同聚集形态的深入探究,能为理解神经退行性病变的分子机制、α-突触核蛋白毒性形式的性质以及α-突触核蛋白聚集影响的信号途径等提供帮助。本文综述目前已知的不同形态α-突触核蛋白结构,阐述α-突触核蛋白单体、寡聚体和不同聚集形式原纤维的结构特征。α-突触核蛋白寡聚体由于其结构不稳定,目前尚无明确的结构信息。但目前已有多个α-突触核蛋白原纤维结构被解析,包括重组蛋白体外制备的和多系统萎缩(MSA)患者体内分离的原纤维。这些原纤维直径由5 nm的单股原纤维至10 nm的双股原纤维不等。不同的体外制备条件可生成不同构象与聚集形式的α-突触核蛋白原纤维,表现出结构异质性。部分家族性PD相关的α-突触核蛋白突变位点位于原纤丝间的相互作用界面。本文依据α-突触核蛋白原纤维中单体的结构和原纤维的组装形式,对α-突触核蛋白原纤维的结构进行分类归纳,以期为探索针对α-突触核蛋白结构的PD诊断与药物开发提供信息。

α-Synuclein(α-syn)aggregates into fibrils to form Lewy bodies(LBs).The Lewy body is a hallmark feature and a pathogenic factor for neurodegenerative diseases,including Parkinson’s disease(PD),multiple system atrophy(MSA)and dementia with Lewy bodies(DLB).Advances in the field of Cryo-electron Microscopy have made it possible to solve the structures ofα-synuclein fibrils at the atomic resolution.The studies of the structure and aggregation ofα-synuclein could provide new perspectives for better understanding the molecular mechanisms for neurodegeneration,the basis for the toxicity ofα-synuclein,and the cellular pathways associated withα-synuclein aggregation.This article reviewed the progress in the field ofα-synuclein,especially,the structures ofα-synuclein monomers,oligomers,and various fibrils.The structures ofα-synuclein were classified according to their monomeric structures and fibril assemblies.Due to its structural flexibility,the structural information for the oligomericα-syn assembly remains elusive.In contrast,different structures ofα-synuclein fibrils have been reported.These fibrils were either reconstituted in vitro under different preparation conditions or obtained from cerebral fluids of MSA patients.The diameter ofα-synuclein fibrils varies from 5 nm in a single-strand protofilament fibril to 10 nm in a double-strand protofilament fibril.The difference and variability inα-synuclein fibril structures emphasize the heterogeneity inα-synuclein fibril structures and cautious in interpretation of these structures.Nevertheless,theseα-synuclein fibril structures can be classified into several categories.Manyα-synuclein mutations associated with familial PD are located at the interface of inter-protofilament.Our review would be helpful for developing structure-based diagnostic and therapeutic strategies targetingα-synuclein in the treatment of PD.