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Nature:与不同疾病相关的突触核蛋白变体

摘要 : 突触核蛋白病是以富含α-突触核蛋白的蛋白沉积为特征的神经退化疾病,包括帕金森氏症、路易氏体型失智症和多系统萎缩症。

 

突触核蛋白病是以富含α-突触核蛋白的蛋白沉积为特征的神经退化疾病,包括帕金森氏症、路易氏体型失智症和多系统萎缩症。具有不同结构特点的α-突触核蛋白聚合体的发现导致人们提出这样一个假说:不同类别的这种蛋白可以解释这些不同神经退化疾病之间的病理差别。这篇研究论文报告说,当不同类别的人α-突触核蛋白(寡聚型、带状型或小纤维型)被活体注射进大鼠脑中时,它们以一种取决于类别的方式传播,造成不同的病理和神经毒性表型。这项研究对于疾病诊断和预后来说以及对于针对特定突触核蛋白病的治疗方案的设计工作的前景来说都是有意义的。

原文链接:

α-Synuclein strains cause distinct synucleinopathies after local and systemic administration

原文摘要:

Misfolded protein aggregates represent a continuum with overlapping features in neurodegenerative diseases, but differences in protein components and affected brain regions1. The molecular hallmark of synucleinopathies such as Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy are megadalton α-synuclein-rich deposits suggestive of one molecular event causing distinct disease phenotypes. Glial α-synuclein (α-SYN) filamentous deposits are prominent in multiple system atrophy and neuronal α-SYN inclusions are found in Parkinson’s disease and dementia with Lewy bodies2. The discovery of α-SYN assemblies with different structural characteristics or ‘strains’ has led to the hypothesis that strains could account for the different clinico-pathological traits within synucleinopathies3, 4. In this study we show that α-SYN strain conformation and seeding propensity lead to distinct histopathological and behavioural phenotypes. We assess the properties of structurally well-defined α-SYN assemblies (oligomers, ribbons and fibrils) after injection in rat brain. We prove that α-SYN strains amplify in vivo. Fibrils seem to be the major toxic strain, resulting in progressive motor impairment and cell death, wheras ribbons cause a distinct histopathological phenotype displaying Parkinson’s disease and multiple system atrophy traits. Additionally, we show that α-SYN assemblies cross the blood–brain barrier and distribute to the central nervous system after intravenous injection. Our results demonstrate that distinct α-SYN strains display differential seeding capacities, inducing strain-specific pathology and neurotoxic phenotypes.

来源: Nature 浏览次数:0

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