Department of Brain Sciences, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
Int J Mol Sci. 2023 Aug 25;24(17):13199. doi: 10.3390/ijms241713199.
Alpha-synucleinopathies (α-synucleinopathies) such as Parkinson's disease (PD), Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are all characterized by aggregates of alpha-synuclein (α-syn), but display heterogeneous clinical and pathological phenotypes. The mechanism underlying this heterogeneity is thought to be due to diversity in the α-syn strains present across the diseases. α-syn obtained from the post-mortem brain of patients who lived with these conditions is heterogenous, and displays a different protease sensitivity, ultrastructure, cytotoxicity, and seeding potential. The primary aim of this review is to summarize previous studies investigating these concepts, which not only reflect the idea of different syn strains being present, but demonstrate that each property explains a small part of a much larger puzzle. Strains of α-syn appear at the center of the correlation between α-syn properties and the disease phenotype, likely influenced by external factors. There are considerable similarities in the properties of disease-specific α-syn strains, but MSA seems to consistently display more aggressive traits. Elucidating the molecular underpinnings of heterogeneity amongst α-synucleinopathies holds promise for future clinical translation, allowing for the development of personalized medicine approaches tackling the root cause of each α-synucleinopathy.
α-突触核蛋白病（α-synucleinopathies），如帕金森病（PD）、帕金森病痴呆（PDD）、路易体痴呆（DLB）和多系统萎缩（MSA），其特征均为α-突触核蛋白（α-syn）聚集，但表现出异质性的临床和病理表型。这种异质性的机制被认为是由于疾病中存在的α-syn 菌株多样性所致。从患有这些疾病的患者死后大脑中获得的α-syn 是异质的，并且表现出不同的蛋白酶敏感性、超微结构、细胞毒性和种籽潜力。本综述的主要目的是总结以前研究这些概念的研究，这些研究不仅反映了不同 syn 菌株存在的观点，而且表明每种特性仅解释了更大谜团的一小部分。α-syn 菌株出现在 α-syn 特性与疾病表型之间相关性的中心，可能受到外部因素的影响。特定疾病的 α-syn 菌株的特性有很多相似之处，但 MSA 似乎始终表现出更具侵略性的特征。阐明 α-突触核蛋白病之间异质性的分子基础有望为未来的临床转化提供帮助，从而开发出针对每种 α-突触核蛋白病根本原因的个性化医疗方法。
