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.

• Authors: Kensuke Daida, Shotaro Shimonaka, Kahori Shiba-Fukushima, Jun Ogata, Hiroyo Yoshino, Ayami Okuzumi, Taku Hatano, Yumiko Motoi, Tomoki Hirunagi, Masahisa Katsuno, Hideo Shindou, Manabu Funayama, Kenya Nishioka, Nobutaka Hattori, Yuzuru Imai
• Journal: Movement disorders : official journal of the Movement Disorder Society (Mov Disord) Vol. 37 Issue 10 Pg. 2075-2085 (10 2022) ISSN: 1531-8257 [Electronic] United States
• PMID: 35894540 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Chemical References

• alpha-Synuclein
• Phospholipids
• SNCA protein, human

Topics

• Humans
• alpha-Synuclein (genetics, metabolism)
• Cell Line
• Mutation, Missense
• Parkinson Disease (metabolism)
• Phospholipids