alpha-Synuclein V15A Variant in Familial Parkinson's Disease Exhibits a Weaker Lipid-Binding Property

Background: The alpha-Synuclein (alpha-Syn) V15A variant has been found in two Caucasian families with Parkinson's disease (PD). However, the significance of this missense variant remained unclear. Objective: We sought to elucidate whether V15A could increase aggregation or change phospholipid affinity. Methods: A sequencing analysis for the SNCA encoding alpha-Syn from 875 patients with PD and 324 control subjects was performed. Comparing with known pathogenicmissense variants of alpha-Syn, A30P, and A53T, we analyzed the effects of V15A on binding to phospholipid membrane, self-aggregation, and seed-dependent aggregation in cultured cells. Results: Genetic screening identified SNCA c.44 T>C (p.V15A) from two Japanese PD families. The missense variant V15A was extremely rare in several public databases and predicted as pathogenic using in silico tools. The amplification activity of alpha-Syn V15A fibrils was stronger than that of wild-type alpha-Syn fibrils. Conclusions: The discovery of the V15A variant from Japanese families reinforces the possibility that the V15A variant may be a causative variant for developing PD. V15A had a reduced affinity for phospholipids and increased propagation activity compared with wild-type. (c) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society