α‐Synuclein V15A Variant in Familial Parkinson's Disease Exhibits a Weaker Lipid‐Binding Property

ABSTRACT Background The α‐Synuclein (α‐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 α‐Syn from 875 patients with PD and 324 control subjects was performed. Comparing with known pathogenic missense variants of α‐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 α‐Syn V15A fibrils was stronger than that of wild‐type α‐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. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society