Effects of N-terminal Acetylation on the Aggregation of Disease-related a-synu- clein Variants

Mutations in the SNCA gene, which encodes the protein a-synuclein, have been linked with early onset Parkinson's disease. The exact nature of this association, however, is still poorly understood. To investi-gate this problem, we started from the observation that a-synuclein is constitutively N-terminally acety-lated, a post-translational modification that alters the charge and structure of a-synuclein molecules and affects their interaction with lipid membranes, as well as their aggregation process. We thus studied five N-terminal acetylated familial variants (A30P, E46K, H50Q, G51D and A53T) of a-synuclein through a wide range of biophysical assays to probe the microscopic steps in their aggregation process and the structures of the resulting aggregates. Our results reveal a great complexity in the combined effects of the disease-related mutations with N-terminal acetylation on the aggregation of a-synuclein, which under-scores the great sensitivity to even relatively small perturbations of the behaviour of this protein.(c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecom-mons.org/licenses/by/4.0/).