小柯机器人

英国剑桥大学Michel Goedert、Sjors H. W. Scheres等研究人员合作揭示路易病理患者脑中的α-突触核蛋白丝结构。相关论文于2022年9月15日在线发表在《自然》杂志上。

研究人员表示，帕金森病（PD）是最常见的运动障碍，静止性震颤、僵硬、运动迟缓和体位不稳是主要症状。在神经病理学上，它的特点是在一些脑细胞（包括黑质的多巴胺能神经细胞）中存在大量的α-突触蛋白的丝状内含物，其形式为路易体和路易神经突。PD越来越被认为是一种多系统的疾病，而认知能力下降是其最常见的非运动症状之一。许多PD患者在确诊后10年以上才发展成痴呆。

帕金森病痴呆（PDD）在临床和神经病理学上与路易体痴呆（DLB）相似，后者是在帕金森病运动症状之前出现认知障碍或在发病后一年内开始出现认知障碍时诊断的。在PDD中，认知障碍是在已确定的PD的情况下发生的。除了PD和DLB，多系统萎缩（MSA）是第三种主要的突触核蛋白病。它的特点是在脑细胞，特别是少突胶质细胞（Papp-Lantos体）中存在大量的丝状α-突触蛋白包裹体。

研究人员以前报道了从MSA患者大脑中提取的两种类型的α-突触核蛋白丝的冷冻电镜（cryo-EM）结构。每种细丝都是由两种不同的原丝组成。研究人员发现，从PD、PDD和DLB患者大脑中提取的α-突触核蛋白丝的cryo-EM结构是由单一的原丝（Lewy折叠）组成的，与MSA的原丝明显不同。这些发现确定了在神经退行性疾病中存在着不同α-突触核蛋白的分子构象。

附：英文原文

Title: Structures of α-synuclein filaments from human brains with Lewy pathology

Author: Yang, Yang, Shi, Yang, Schweighauser, Manuel, Zhang, Xianjun, Kotecha, Abhay, Murzin, Alexey G., Garringer, Holly J., Cullinane, Patrick W., Saito, Yuko, Foroud, Tatiana, Warner, Thomas T., Hasegawa, Kazuko, Vidal, Ruben, Murayama, Shigeo, Revesz, Tamas, Ghetti, Bernardino, Hasegawa, Masato, Lashley, Tammaryn, Scheres, Sjors H. W., Goedert, Michel

Issue&Volume: 2022-09-15

Abstract: Parkinson’s disease (PD) is the most common movement disorder, with resting tremor, rigidity, bradykinesia and postural instability being major symptoms (1). Neuropathologically, it is characterised by the presence of abundant filamentous inclusions of α-synuclein in the form of Lewy bodies and Lewy neurites in some brain cells, including dopaminergic nerve cells of the substantia nigra (2). PD is increasingly recognised as a multisystem disorder, with cognitive decline being one of its most common non-motor symptoms. Many patients with PD develop dementia more than 10 years after diagnosis (3). PD dementia (PDD) is clinically and neuropathologically similar to dementia with Lewy bodies (DLB), which is diagnosed when cognitive impairment precedes parkinsonian motor signs or begins within one year from their onset (4). In PDD, cognitive impairment develops in the setting of well-established PD. Besides PD and DLB, multiple system atrophy (MSA) is the third major synucleinopathy (5). It is characterised by the presence of abundant filamentous α-synuclein inclusions in brain cells, especially oligodendrocytes (Papp-Lantos bodies). We previously reported the electron cryo-microscopy (cryo-EM) structures of two types of α-synuclein filaments extracted from the brains of individuals with MSA (6). Each filament type is made of two different protofilaments. Here we report that the cryo-EM structures of α-synuclein filaments from the brains of individuals with PD, PDD and DLB are made of a single protofilament (Lewy fold) that is markedly different from the protofilaments of MSA. These findings establish the existence of distinct molecular conformers of assembled α-synuclein in neurodegenerative disease.

DOI: 10.1038/s41586-022-05319-3

Source: https://www.nature.com/articles/s41586-022-05319-3

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