α-Synuclein V15A Variant in Familial Parkinson's Disease Exhibits a Weaker Lipid-Binding Property.
α-Synuclein V15A Variant in Familial Parkinson's Disease Exhibits a Weaker Lipid-Binding Property.
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DOI：
10.1002/mds.29162
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发表时间：
2022-10
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α-Synuclein（α-Syn）V15 A变体已在两个患有帕金森病（PD）的白人家族中发现。然而，这种错义变体的意义仍然不清楚。我们试图阐明V15 A是否可以增加聚集或改变磷脂亲和力。对875例PD患者和324例对照受试者的编码α-Syn的SNCA进行测序分析。与已知的α-Syn、A30 P和A53 T的致病性错义变体相比，我们分析了V15 A对培养细胞中磷脂膜结合、自聚集和种子依赖性聚集的影响。遗传筛查从两个日本PD家族中鉴定出SNCA c.44 T>C（p.V15A）。错义变体V15 A在几个公共数据库中非常罕见，并使用计算机工具预测为致病性。α-Syn V15 A原纤维的扩增活性比野生型α-Syn原纤维强。来自日本家族的V15 A变异的发现加强了V15 A变异可能是发展PD的致病变异的可能性。与野生型相比，V15 A对磷脂的亲和力降低，繁殖活性增加。版权所有© 2022作者。运动障碍由Wiley Periodicals LLC代表国际帕金森和运动障碍协会出版
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. We sought to elucidate whether V15A could increase aggregation or change phospholipid affinity. 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. 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. 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