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

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 a-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 a-synuclein in solution, but weakens its affinity for membranes. Attenuated membrane binding raises the concentration of the aggregation-prone disordered a-synuclein in solution, allowing only the V15A variant but not wild-type a-synuclein to form amyloid fibrils in the presence of liposomes. These findings, together with earlier research on other missense mutations of a-synuclein, suggest that maintaining a balance between membrane-bound and free aggregation-competent a-synuclein is critical in a-synucleinopathies.

Automated summary

Parkinson's disease can be either sporadic or inherited, with missense mutations causing the inherited form. The V15A mutation of alpha-synuclein weakens its affinity for membranes but does not significantly affect its conformation in solution. This leads to increased concentration of aggregation-prone alpha-synuclein, allowing the V15A variant to form amyloid fibrils. These findings underscore the importance of maintaining a balance between membrane-bound and free aggregation-competent alpha-synuclein in synucleinopathies.