Cellular and Molecular Neurobiology
Author: Fiamma Ayelen Buratti | Email: firstname.lastname@example.org
Fiamma Ayelen Buratti 1°, Markus Zweckstetter 2°, Claudio Oscar Fernández 1°
1° Max Planck Laboratory for Structural Biology, Chemistry, and Molecular Biophysics of Rosario (MPLbioR, UNR-MPINAT), Partner Laboratory of the Max Planck Institute for Multidisciplinary Sciences (MPINAT, MPG). Centro de Estudios Interdisciplinarios, Universidad Nacional de Rosario, Rosario, Argentina.
2° German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075 Göttingen, Germany.
Parkinson’s disease can manifest either as a sporadic form, which is common or as an inherited autosomal dominant trait resulting from missense mutations. Nine potentially pathogenic variants of α-synuclein (αSyn) associated with familial PD have been identified to date. This includes the well-studied A30P, E46K and A53T variants, as well as A30G, H50Q, G51D, A53E, and A53V. Recently, the novel ɑ-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 ɑ-synuclein in solution, but weakens its affinity for membranes. Attenuated membrane binding raises the concentration of the aggregation-prone disordered ɑ-synuclein in solution, allowing only the V15A variant but not wild-type ɑ-synuclein to form amyloid fibrils in the presence of liposomes. These findings, together with earlier research on other missense mutations of ɑ-synuclein, suggest that maintaining a balance between membrane-bound and free aggregation-competent ɑ-synuclein is critical in ɑ-synucleinopathies.