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Assessing the impact of N-terminal acetylation on the aggregation of alpha-synuclein and its disease-related mutants 10.17863/CAM.87660 Bell, Rosie 0000000217447066 Vendruscolo, Michele Dobson, Christopher Parkinson’s disease is associated with the aberrant aggregation of α-synuclein within neurons. Although the causes of this process are still unclear, post-translational modifications of α-synuclein are likely to play a modulatory role. Since α-synuclein is constitutively N-terminally acetylated, we investigated how this post-translational modification alters the aggregation behaviour of this protein. By applying a three-pronged aggregation kinetics approach, we observed that N-terminal acetylation results in a reduced rate of lipid-induced aggregation and in a slowing down of both elongation and fibril-catalysed aggregate proliferation. An analysis of the amyloid fibrils produced by the aggregation process revealed different morphologies for the acetylated and non-acetylated forms in both the lipid-induced aggregation and seed-induced aggregation assays. In addition, we found that fibrils formed by acetylated α-synuclein possess a lower β-sheet content. These findings indicate that N-terminal acetylation of α-synuclein alters its lipid-dependent aggregation behaviour, reduces its rate of in vitro aggregation, and affects the structural properties of its fibrillar aggregates. We then investigated how this modification affects the α-synuclein mutants associated with familial Parkinson’s disease. We found that all N-terminal acetylated mutants were capable of forming seeding-competent, amyloid-like aggregates in the presence of lipid vesicles. These results are relevant as lipid membranes could stimulate the initial nucleation process that leads to the aggregation of α-synuclein in vivo. In perspective, the set of assays that we have developed can be taken forward and used to investigate how other post-translational modifications can impact the behaviour of α-synuclein. University of Cambridge 2021-12-21 Thesis Doctoral Doctor of Philosophy (PhD) eng RG74039, MBAG/057, T1. https://www.repository.cam.ac.uk/handle/1810/340234 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/9d8a6535-a874-43fc-8de0-e19609cbf91e/download 186ab252a4b9ec4802820ab955bb2b70 https://www.rioxx.net/licenses/all-rights-reserved/ alpha-synuclein Parkinson's disease Familial Parkinson's disease amyloid aggregation Biophysics