Alpha-synuclein (αSyn) plays a central role in the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In sporadic PD and DLB, normally harmless αSyn proteins without any mutations might gain toxic functions by unknown mechanisms. Thus, it is important to elucidate the factors promoting the toxic conversion of αSyn, towards understanding the pathogenesis of and developing disease-modifying therapies for PD and DLB. Accumulating biophysical and biochemical studies have demonstrated that αSyn interacts with lipid membrane, and the interaction influences αSyn oligomerization and aggregation. Furthermore, genetic and clinicopathological studies have revealed mutations in the glucocerebrosidase 1 (GBA1) gene, which encodes a degrading enzyme for the glycolipid glucosylceramide (GlcCer), as strong risk factors for PD and DLB, and we recently demonstrated that GlcCer promotes toxic conversion of αSyn. Moreover, pathological studies have shown the existence of αSyn pathology in lysosomal storage disorders (LSDs) patient’ brain, in which glycosphingolipids (GSLs) is found to be accumulated. In this review, we focus on the lipids as a key factor for inducing wild-type (WT) αSyn toxic conversion, we summarize the knowledge about the interaction between αSyn and lipid membrane, and propose our hypothesis that aberrantly accumulated GSLs might contribute to the toxic conversion of αSyn. Identifying the trigger for toxic conversion of αSyn would open a new therapeutic road to attenuate or prevent crucial events leading to the formation of toxic αSyn.

α-突触核蛋白（αSyn）在帕金森氏病（PD）和路易小体（DLB）痴呆的发病机理中起着核心作用。在散发的PD和DLB中，通常无害的无任何突变的αSyn蛋白可能会通过未知机制获得毒性功能。因此，重要的是要阐明促进αSyn毒性转化的因素，以了解PD和DLB的发病机理并开发改善疾病的疗法。越来越多的生物物理和生化研究表明，αSyn与脂质膜相互作用，并且这种相互作用影响αSyn的寡聚和聚集。此外，遗传和临床病理学研究表明，葡萄糖脑苷脂酶1（GBA1）基因，它编码糖脂葡糖神经酰胺（GlcCer）的降解酶，是PD和DLB的强大危险因素，最近我们证明了GlcCer可以促进αSyn的毒性转化。此外，病理研究表明，在溶酶体贮积症（LSDs）患者的大脑中存在αSyn病理，其中发现了糖鞘脂（GSL）积累。在这篇综述中，我们集中于脂质作为诱导野生型（WT）αSyn毒性转化的关键因素，我们总结了有关αSyn与脂质膜之间相互作用的知识，并提出了我们的假设，即异常积累的GSLs可能有助于αSyn的有毒转化。确定αSyn毒性转化的诱因将为减轻或预防导致毒性αSyn形成的关键事件开辟一条新的治疗之路。