α-Synuclein strains cause distinct synucleinopathies after local and systemic administration
α-Synuclein strains cause distinct synucleinopathies after local and systemic administration
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DOI：
10.1038/nature14547
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发表时间：
2015-06-18
期刊：
影响因子：
64.8
通讯作者：
Baekelandt, V.
中科院分区：
文献类型：
--
作者：
Peelaerts, W.;Bousset, L.;Baekelandt, V.
错误折叠的蛋白质聚集体在神经退行性疾病中代表了一个具有重叠特征的连续体，但蛋白质成分和受影响的大脑区域存在差异(1)。帕金森氏病、路易体痴呆和多系统萎缩等共核病的分子标志是富含α-突触核蛋白的巨型沉淀物，提示一个分子事件导致了不同的疾病表型。神经胶质α-突触核蛋白(α-SYN)丝状沉积在多系统萎缩中显著，在帕金森氏病和路易小体痴呆中发现神经元α-SYN包涵体。具有不同结构特征或‘菌株’的α-SYN组件的发现导致了一种假说，即菌株可以解释联核病中不同的临床病理特征(3，4)。在这项研究中，我们表明，α-SYN株的构象和播种倾向导致了不同的组织病理和行为表型。我们评估了大鼠脑内注射后结构明确的α-SYN组件(寡聚体、条带和纤维)的性质。我们证明了α-SYN菌株在体内可以扩增。纤维似乎是主要的毒性应变，导致进行性运动障碍和细胞死亡，而丝带导致明显的组织病理表型，表现为帕金森氏病和多系统萎缩特征。此外，我们还发现，在静脉注射后，α-SYN集合体穿过血脑屏障并分布到中枢神经系统。我们的结果表明，不同的α-SYN菌株表现出不同的播种能力，诱导菌株特有的病理和神经毒性表型。
Misfolded protein aggregates represent a continuum with overlapping features in neurodegenerative diseases, but differences in protein components and affected brain regions(1). The molecular hallmark of synucleinopathies such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are megadalton alpha-synuclein-rich deposits suggestive of one molecular event causing distinct disease phenotypes. Glial alpha-synuclein (alpha-SYN) filamentous deposits are prominent in multiple system atrophy and neuronal alpha-SYN inclusions are found in Parkinson's disease and dementia with Lewy bodies(2). The discovery of alpha-SYN assemblies with different structural characteristics or 'strains' has led to the hypothesis that strains could account for the different clinicopathological traits within synucleinopathies(3,4). In this study we show that alpha-SYN strain conformation and seeding propensity lead to distinct histopathological and behavioural phenotypes. We assess the properties of structurally well-defined alpha-SYN assemblies (oligomers, ribbons and fibrils) after injection in rat brain. We prove that alpha-SYN strains amplify in vivo. Fibrils seem to be the major toxic strain, resulting in progressive motor impairment and cell death, whereas ribbons cause a distinct histopathological phenotype displaying Parkinson's disease and multiple system atrophy traits. Additionally, we show that alpha-SYN assemblies cross the blood-brain barrier and distribute to the central nervous system after intravenous injection. Our results demonstrate that distinct alpha-SYN strains display differential seeding capacities, inducing strain-specific pathology and neurotoxic phenotypes.