Functional Study of SNCA p.V15A Variant: Further Linking α‐Synuclein and Glucocerebrosidase

• Published in: Movement disorders 2024-06, Vol.39 (6), p.1060-1065
• Main Authors: Avenali, Micol, Cerri, Silvia, Palmieri, Ilaria, Ongari, Gerardo, Stiuso, Rita, Buongarzone, Gabriele, Tassorelli, Cristina, Biagini, Tommaso, Valente, Marialuisa, Cereda, Cristina, Mazza, Tommaso, Gana, Simone, Pacchetti, Claudio, Valente, Enza Maria
• Format: Article
• Language: English
• Subjects: Age composition; Aged; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Apoptosis; Female; functional characterization; Genetic screening; glucocerebrosidase; Glucosylceramidase; Glucosylceramidase - genetics; Humans; Leukocytes (mononuclear); Leukocytes, Mononuclear - metabolism; Male; Middle Aged; Molecular dynamics; Movement disorders; Mutants; Mutation - genetics; Neurodegenerative diseases; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson's disease; Pathogenicity; Pedigree; Peripheral blood mononuclear cells; Protein seeding; Protein structure; SNCA gene; Synuclein; α‐synuclein
• ISSN: 0885-3185; 1531-8257; 1531-8257
• DOI: 10.1002/mds.29736

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. Objectives 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. Conclusion 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.