Parkinson's disease‐linked V15A mutation facilitates α‐synuclein aggregation by reducing membrane affinity

Abstract

AbstractParkinson's disease can manifest either as a sporadic form, which is common, or as an inherited autosomal dominant trait resulting from missense mutations. Recently, the novel α‐synuclein variant V15A was identified in two Caucasian and two Japanese families with Parkinson's disease. Using a combination of NMR spectroscopy, membrane binding assays and aggregation assays we show that the V15A mutation does not strongly perturb the conformational ensemble of monomeric α‐synuclein in solution, but weakens its affinity for membranes. Attenuated membrane binding raises the concentration of the aggregation‐prone disordered α‐synuclein in solution, allowing only the V15A variant but not wild‐type α‐synuclein to form amyloid fibrils in the presence of liposomes. These findings, together with earlier research on other missense mutations of α‐synuclein, suggest that maintaining a balance between membrane‐bound and free aggregation‐competent α‐synuclein is critical in α‐synucleinopathies.