nn9b09676_si_001.pdf (1.54 MB)
The Influence of Pathogenic Mutations in α‑Synuclein on Biophysical and Structural Characteristics of Amyloid Fibrils
journal contribution
posted on 2020-03-17, 12:04 authored by Francesco
Simone Ruggeri, Patrick Flagmeier, Janet R. Kumita, Georg Meisl, Dimitri Y. Chirgadze, Marie N. Bongiovanni, Tuomas P. J. Knowles, Christopher M. DobsonProteinaceous deposits
of α-synuclein amyloid fibrils are
a hallmark of human disorders including Parkinson’s disease.
The onset of this disease is also associated with five familial mutations
of the gene encoding the protein. However, the mechanistic link between
single point mutations and the kinetics of aggregation, biophysical
properties of the resulting amyloid fibrils, and an increased risk
of disease is still elusive. Here, we demonstrate that the disease-associated
mutations of α-synuclein generate different amyloid fibril polymorphs
compared to the wild type protein. Remarkably, the α-synuclein
variants forming amyloid fibrils of a comparable structure, morphology,
and heterogeneity show similar microscopic steps defining the aggregation
kinetics. These results demonstrate that a single point mutation can
significantly alter the distribution of fibrillar polymorphs in α-synuclein,
suggesting that differences in the clinical phenotypes of familial
Parkinson’s disease could be associated with differences in
the mechanism of formation and the structural characteristics of the
aggregates.