Characterization of the pathogenic α-Synuclein Variant V15A in Parkinson´s disease

Sokhna Haissatou Diaw, Max Borsche, Linn Streubel-Gallasch, Marija Dulovic-Mahlow, Julia Hermes, Insa Lenz, Philip Seibler, Christine Klein, Norbert Brüggemann, Melissa Vos, Katja Lohmann*

*Korrespondierende/r Autor/-in für diese Arbeit

Abstract

Despite being a major component of Lewy bodies and Lewy neurites, pathogenic variants in the gene encoding alpha-Synuclein (α-Syn) are rare. To date, only four missense variants in the SNCA gene, encoding α-Syn have unequivocally been shown to be disease-causing. We here describe a Parkinson´s disease patient with early cognitive decline carrying an as yet not fully characterized variant in SNCA (NM_001146055: c.44T > C, p.V15A). We used different cellular models, including stably transfected neuroblastoma (SH-SY5Y) cell cultures, induced pluripotent stem cell (iPSC)-derived neuronal cultures, and generated a Drosophila model to elucidate the impact of the p.V15A variant on α-Syn function and aggregation properties compared to other known pathogenic variants. We demonstrate that p.V15A increased the aggregation potential of α-Syn and the levels of apoptotic markers, and impaired the mitochondrial network. Moreover, p.V15A affects the flying ability and survival of mutant flies. Thus, we provide supporting evidence for the pathogenicity of the p.V15A variant, suggesting its inclusion in genetic testing approaches.

OriginalspracheEnglisch
Aufsatznummer148
ZeitschriftNPJ Parkinson's disease
Jahrgang9
Ausgabenummer1
ISSN2373-8057
DOIs
PublikationsstatusVeröffentlicht - 12.2023

Strategische Forschungsbereiche und Zentren

  • Querschnittsbereich: Medizinische Genetik

DFG-Fachsystematik

  • 206-06 Molekulare und Zelluläre Neurologie und Neuropathologie

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