Effects of N-terminal Acetylation on the Aggregation of Disease-related α-synuclein Variants
Rosie Bella, Marta Castellana-Cruza, Aishwarya Nenea, Rebecca J. Thrusha, Catherine K. Xua, Janet R. Kumitab c✉, Michele Vendruscoloa d✉
- aCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
- bDepartment of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK. Electronic address: jrk38@cam.ac.uk
- cDepartment of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK
- dCentre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK. Electronic address: mv245@cam.ac.uk
- ✉Corresponding author
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Abstract
Mutations in the SNCA gene, which encodes the protein α-synuclein, have been linked with early onset Parkinson's disease. The exact nature of this association, however, is still poorly understood. To investigate this problem, we started from the observation that α-synuclein is constitutively N-terminally acetylated, a post-translational modification that alters the charge and structure of α-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 α-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 α-synuclein, which underscores the great sensitivity to even relatively small perturbations of the behaviour of this protein.
TL;DRA great complexity is revealed in the combined effects of the disease-related mutations with N-terminal acetylation on the aggregation of α-synuclein, which underscores the great sensitivity to even relatively small perturbations of the behaviour of this protein. (Semantic Scholar)