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

Abstract

Parkinson'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.