Alpha-synuclein is an intrinsically disordered, highly dynamic protein that pathogenically aggregates into inclusion structures called Lewy bodies, in several neurogenerative diseases termed synucleinopathies. Despite its importance for understanding disease, the oligomerization status of alpha-synuclein in healthy cells remains unclear. Alpha-synuclein may exist predominantly as either a monomer or a variety of oligomers of different molecular weights. There is solid evidence to support both theories. Detection of apparent endogenous oligomers are intimately dependent on vesicle and lipid interactions. Here we consider the possibility that apparent endogenous alpha-synuclein oligomers are in fact conformations of membrane-bound alpha-synuclein and not a bona fide stable soluble species. This perspective posits that the formation of any alpha-synuclein oligomers within the cell is likely toxic and interconversion between monomer and oligomer is tightly controlled. This differs from the hypothesis that there is a continuum of endogenous non-toxic oligomers and they convert, through unclear mechanisms, to toxic oligomers. The distinction is important, because it clarifies the biological origin of synucleinopathy. We suggest that a monomer-only, lipid-centric view of endogenous alpha-synuclein aggregation can explain how alpha-synuclein pathology is triggered, and that the interactions between alpha-synuclein and lipids can represent a target for therapeutic intervention. This discussion is well-timed due to recent studies that show lipids are a significant component of Lewy pathology.

α-突触核蛋白是一种内在失调的，高度动态的蛋白，在几种称为神经突触病的神经发生性疾病中，其病原性地聚集成称为路易体的包涵结构。尽管它对于理解疾病很重要，但是在健康细胞中α-突触核蛋白的低聚状态仍然不清楚。α-突触核蛋白可以主要以单体或多种不同分子量的低聚物的形式存在。有确凿的证据支持这两种理论。表观内源性低聚物的检测与囊泡和脂质的相互作用密切相关。在这里，我们考虑表观内源性α-突触核蛋白低聚物实际上是膜结合α-突触核蛋白的构象，而不是真正稳定的可溶性物种的可能性。该观点认为，细胞内任何α-突触核蛋白低聚物的形成可能是有毒的，并且单体与低聚物之间的相互转化受到严格控制。这不同于假设，即存在连续的内源性无毒低聚物，并且它们通过不清楚的机理转化为有毒低聚物。区别很重要，因为它阐明了突触核蛋白病的生物学起源。我们建议内源性α-突触核蛋白聚集的仅单体，以脂质为中心的观点可以解释α-突触核蛋白病理学是如何被触发的，并且α-突触核蛋白与脂质之间的相互作用可以代表治疗干预的目标。由于最近的研究表明脂质是路易氏病理学的重要组成部分，因此该讨论时机适当。