Pathological role of lipid interaction with α-synuclein in Parkinson's disease

Alpha-synuclein (alpha Syn) 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 alpha Syn proteins without any mutations might gain toxic functions by unknown mechanisms. Thus, it is important to elucidate the factors promoting the toxic conversion of alpha Syn, towards understanding the pathogenesis of and developing disease-modifying therapies for PD and DLB. Accumulating biophysical and biochemical studies have demonstrated that alpha Syn interacts with lipid membrane, and the interaction influences alpha Syn 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 (GIcCer), as strong risk factors for PD and DLB, and we recently demonstrated that GIcCer promotes toxic conversion of alpha Syn. Moreover, pathological studies have shown the existence of alpha Syn 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) alpha Syn toxic conversion, we summarize the knowledge about the interaction between alpha Syn and lipid membrane, and propose our hypothesis that aberrantly accumulated GSLs might contribute to the toxic conversion of alpha Syn. Identifying the trigger for toxic conversion of alpha Syn would open a new therapeutic road to attenuate or prevent crucial events leading to the formation of toxic alpha Syn. (C) 2018 The Authors. Published by Elsevier Ltd.