Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada; Department of Biochemistry, University of Toronto, Toronto, ON, Canada. Electronic address: https://twitter.com/xsakuraphie.
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada; Department of Biochemistry, University of Toronto, Toronto, ON, Canada. Electronic address: https://twitter.com/JoelWattsLab.
J Mol Biol. 2023 Jun 15;435(12):168011. doi: 10.1016/j.jmb.2023.168011. Epub 2023 Feb 13.
The synucleinopathies, which include Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are a class of human neurodegenerative disorders unified by the presence of α-synuclein aggregates in the brain. Considerable clinical and pathological heterogeneity exists within and among the individual synucleinopathies. A potential explanation for this variability is the existence of distinct conformational strains of α-synuclein aggregates that cause different disease manifestations. Like prion strains, α-synuclein strains can be delineated based on their structural architecture, with structural differences among α-synuclein aggregates leading to unique biochemical attributes and neuropathological properties in humans and animal models. Bolstered by recent high-resolution structural data from patient brain-derived material, it has now been firmly established that there are conformational differences among α-synuclein aggregates from different human synucleinopathies. Moreover, recombinant α-synuclein can be polymerized into several structurally distinct aggregates that exhibit unique pathological properties. In this review, we outline the evidence supporting the existence of α-synuclein strains and highlight how they can act as drivers of phenotypic heterogeneity in the human synucleinopathies.
突触核蛋白病包括帕金森病、路易体痴呆和多系统萎缩，是以脑内存在α-突触核蛋白聚集为特征的一类人类神经退行性疾病。在个体突触核蛋白病内部和之间存在相当大的临床和病理异质性。这种可变性的一个潜在解释是存在不同构象的α-突触核蛋白聚集，导致不同的疾病表现。与朊病毒株类似，α-突触核蛋白株可以根据其结构架构进行划分，α-突触核蛋白聚集的结构差异导致人类和动物模型中独特的生化特征和神经病理学特性。最近来自患者脑源性物质的高分辨率结构数据的支持，现在已经明确不同人类突触核蛋白病的α-突触核蛋白聚集存在构象差异。此外，重组α-突触核蛋白可以聚合为几种结构上明显不同的聚集物，表现出独特的病理特性。在这篇综述中，我们概述了支持α-突触核蛋白株存在的证据，并强调了它们如何作为人类突触核蛋白病表型异质性的驱动因素。
