{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/340234"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/340234","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Assessing the impact of N-terminal acetylation on the aggregation of alpha-synuclein and its disease-related mutants","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Bell, Rosie"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Vendruscolo, Michele","Dobson, Christopher"],"committee_chairs":[],"committee_members":[],"year":2021,"date_issued":"2021-12-21","date_published":"2021-12-21","updated_at":"2026-07-22T22:24:28Z","subjects":["alpha-synuclein","Parkinson's disease","Familial Parkinson's disease","amyloid aggregation","Biophysics"],"languages":["eng"],"rights":[],"rights_urls":["https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000217447066"],"render_values":[{"text":"0000-0002-1744-7066","href":"https://orcid.org/0000-0002-1744-7066","code":true}]}]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.87660","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Vendruscolo, Michele","Dobson, Christopher"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["RG74039, MBAG/057, T1."]},{"key":"dc:creator","label":"Author","values":["Bell, Rosie"]},{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000217447066"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2021-12-21"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/340234"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["alpha-synuclein","Parkinson's disease","Familial Parkinson's disease","amyloid aggregation","Biophysics"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://www.rioxx.net/licenses/all-rights-reserved/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["10.17863/CAM.87660"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/9d8a6535-a874-43fc-8de0-e19609cbf91e/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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."]},{"key":"dc:format.checksum.md5","label":"Dc Format Checksum Md5","values":["186ab252a4b9ec4802820ab955bb2b70"]},{"key":"dc:title","label":"Title","values":["Assessing the impact of N-terminal acetylation on the aggregation of alpha-synuclein and its disease-related mutants"]}]}],"canonical_facts":{"dc:contributor.advisor":["Vendruscolo, Michele","Dobson, Christopher"],"dc:contributor.sponsor":["RG74039, MBAG/057, T1."],"dc:creator":["Bell, Rosie"],"dc:creator.authoridentifier":["0000000217447066"],"dc:date.issued":["2021-12-21"],"dc:description.abstract":["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. 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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."],"dc:format.checksum.md5":["186ab252a4b9ec4802820ab955bb2b70"],"dc:identifier.doi":["10.17863/CAM.87660"],"dc:identifier.uri":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/9d8a6535-a874-43fc-8de0-e19609cbf91e/download"],"dc:language":["eng"],"dc:publisher.institution":["University of Cambridge"],"dc:relation.isreferencedby.uri":["https://www.repository.cam.ac.uk/handle/1810/340234"],"dc:rights":["https://www.rioxx.net/licenses/all-rights-reserved/"],"dc:subject":["alpha-synuclein","Parkinson's disease","Familial Parkinson's disease","amyloid aggregation","Biophysics"],"dc:title":["Assessing the impact of N-terminal acetylation on the aggregation of alpha-synuclein and its disease-related mutants"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["Doctoral"],"dc:type.qualificationname":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-22T22:24:28Z"}