Structures of α-synuclein filaments from human brains with Lewy pathology.
Structures of α-synuclein filaments from human brains with Lewy pathology.
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DOI：
10.1038/s41586-022-05319-3
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发表时间：
2022-10
期刊：
影响因子：
64.8
通讯作者：
Goedert M
中科院分区：
文献类型：
--
作者：
Yang Y;Shi Y;Schweighauser M;Zhang X;Kotecha A;Murzin AG;Garringer HJ;Cullinane PW;Saito Y;Foroud T;Warner TT;Hasegawa K;Vidal R;Murayama S;Revesz T;Ghetti B;Hasegawa M;Lashley T;Scheres SHW;Goedert M
帕金森病（PD）是最常见的运动障碍，以静止性震颤、强直、运动迟缓和姿势不稳为主要症状。在神经病理学上，其特征是一些脑细胞（包括黑质的多巴胺能神经细胞）中存在丰富的路易体和路易神经突形式的α-突触核蛋白丝状内含物。帕金森病越来越被认为是一种多系统疾病，认知能力下降是其最常见的非运动症状之一。许多 PD 患者在诊断后 10 多年才出现痴呆。 PD 痴呆 (PDD) 在临床和神经病理学上与路易体痴呆 (DLB) 相似，当认知障碍先于帕金森运动症状或在发病后一年内开始时，即可诊断为路易体痴呆。在 PDD 中，认知障碍是在已确定的 PD 背景下发生的。除了PD和DLB之外，多系统萎缩（MSA）是第三种主要的突触核蛋白病。其特征是脑细胞，特别是少突胶质细胞（帕普-兰托斯小体）中存在丰富的丝状 α-突触核蛋白内含物。我们之前报道了从 MSA 患者大脑中提取的两种 α-突触核蛋白丝的电子冷冻显微镜 (cryo-EM) 结构。每种细丝类型均由两种不同的原丝制成。在这里，我们报告说，来自 PD、PDD 和 DLB 患者大脑的 α-突触核蛋白丝的冷冻电镜结构由单个原丝（路易折叠）组成，该原丝与 MSA 的原丝明显不同。这些发现证实了神经退行性疾病中组装的 α-突触核蛋白存在不同的分子构象异构体。
Parkinson’s disease (PD) is the most common movement disorder, with resting tremor, rigidity, bradykinesia and postural instability being major symptoms. 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. 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. 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. 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. 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. 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.
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影响因子：
2.5
作者：
Crowther, RA;Daniel, SE;Goedert, M
通讯作者：
Goedert, M
影响因子：
2.9
作者：
Conway, KA;Harper, JD;Lansbury, PT
通讯作者：
Lansbury, PT
影响因子：
16.2
作者：
GOEDERT, M;SPILLANTINI, MG;CROWTHER, RA
通讯作者：
CROWTHER, RA
影响因子：
7.7
作者：
Lövestam S;Koh FA;van Knippenberg B;Kotecha A;Murzin AG;Goedert M;Scheres SHW
通讯作者：
Scheres SHW
影响因子：
8.6
作者：
Berg, Daniela;Postuma, Ronald B.;Bloem, Bastiaan;Chan, Piu;Dubois, Bruno;Gasser, Thomas;Goetz, Christopher G.;Halliday, Glenda M.;Hardy, John;Lang, Anthony E.;Litvan, Irene;Marek, Kenneth;Obeso, Jose;Oertel, Wolfgang;Olanow, C. Warren;Poewe, Werner;Stern, Matthew;Deuschl, Guenther
通讯作者：
Deuschl, Guenther