背景：SNCAp.V15A在五个家庭中报道。体外模型显示增加的聚集和接种活性，线粒体损伤，和凋亡。突变果蝇的飞行能力和存活率降低。
目的：在临床和功能上评估患有帕金森病（PD）的意大利大型家庭的SNCAp.V15A。
方法：通过下一代测序达到遗传诊断。通过分子动力学模拟和外周血单核细胞（PBMC）的生化研究评估致病性。
结果：五个兄弟姐妹携带SNCAp.V15A；三个人在50多岁时发展为缓慢运动-刚性PD，具有快速的运动进展和可变的认知障碍。第四个兄弟姐妹有孤立的情绪障碍，而第五个在47岁时仍未受影响。突变蛋白显示出降低的稳定性和不稳定的折叠结构。Proband的PBMC显示总和磷酸化的α-突触核蛋白（α-syn）水平升高，并显着降低葡萄糖脑苷脂酶活性。
结论：这项研究表明，α-synV15A在PBMC中的积累，并加强了α-syn病理生理学与葡糖脑苷脂酶功能障碍之间的联系。©2024作者由WileyPeriodicalsLLC代表国际帕金森症和运动障碍协会出版的运动障碍。
BACKGROUND: SNCA p.V15A was reported in five families. In vitro models showed increased aggregation and seeding activity, mitochondrial damage, and apoptosis. Mutant flies had reduced flying ability and survival.
OBJECTIVE: To clinically and functionally evaluate SNCA p.V15A in a large Italian family with Parkinson\'s disease (PD).
METHODS: Genetic diagnosis was reached through next-generation sequencing. Pathogenicity was assessed by molecular dynamics simulation and biochemical studies on peripheral blood mononuclear cells (PBMCs).
RESULTS: Five siblings carried SNCA p.V15A; three developed bradykinetic-rigid PD in their 50s with rapid motor progression and variable cognitive impairment. A fourth sibling had isolated mood disturbance, whereas the fifth was still unaffected at age 47. The mutant protein showed decreased stability and an unstable folded structure. Proband\'s PBMCs showed elevated total and phosphorylated α-synuclein (α-syn) levels and significantly reduced glucocerebrosidase activity.
CONCLUSIONS: This
study demonstrates accumulation of α-synV15A in PBMCs and strengthens the link between α-syn pathophysiology and glucocerebrosidase dysfunction. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
