Beschreibung:
<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>SNCA</jats:italic> 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 <jats:italic>SNCA</jats:italic> (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 <jats:italic>Drosophila</jats:italic> 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.</jats:p>