{"doi":"10.1016/j.neuron.2023.11.020","title":"Serine-129 phosphorylation of α-synuclein is an activity-dependent trigger for physiologic protein-protein interactions and synaptic function","abstract":"Phosphorylation of α-synuclein at the serine-129 site (α-syn Ser129P) is an established pathologic hallmark of synucleinopathies and a therapeutic target. In physiologic states, only a fraction of α-syn is phosphorylated at this site, and most studies have focused on the pathologic roles of this post-translational modification. We found that unlike wild-type (WT) α-syn, which is widely expressed throughout the brain, the overall pattern of α-syn Ser129P is restricted, suggesting intrinsic regulation. Surprisingly, preventing Ser129P blocked activity-dependent synaptic attenuation by α-syn-thought to reflect its normal function. Exploring mechanisms, we found that neuronal activity augments Ser129P, which is a trigger for protein-protein interactions that are necessary for mediating α-syn function at the synapse. AlphaFold2-driven modeling and membrane-binding simulations suggest a scenario where Ser129P induces conformational changes that facilitate interactions with binding partners. Our experiments offer a new conceptual platform for investigating the role of Ser129 in synucleinopathies, with implications for drug development.","journal":"Neuron","year":2023,"id":315820,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":133,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9537,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":441273,"name":"Kayalvizhi Madhivanan","orcid":"0000-0002-4241-2922","position":1,"is_corresponding":false},{"id":459241,"name":"Brent Aulston","orcid":"0000-0001-6865-0577","position":2,"is_corresponding":false},{"id":1018095,"name":"Lina Wang","orcid":"0000-0001-6294-7310","position":3,"is_corresponding":false},{"id":1019058,"name":"Dube Dheeraj Prakashchand","orcid":null,"position":4,"is_corresponding":false},{"id":542506,"name":"Nicholas P. Boyer","orcid":"0000-0001-8283-1710","position":5,"is_corresponding":false},{"id":1018096,"name":"Verônica M. Saia‐Cereda","orcid":"0000-0002-6285-1201","position":6,"is_corresponding":false},{"id":1018097,"name":"Kristen Branes‐Guerrero","orcid":"0000-0002-2181-2425","position":7,"is_corresponding":false},{"id":335161,"name":"Donald Pizzo","orcid":"0000-0002-8022-3604","position":8,"is_corresponding":false},{"id":741066,"name":"Pritha Bagchi","orcid":"0000-0001-7229-9476","position":9,"is_corresponding":false},{"id":1019059,"name":"V. S. Sundar","orcid":null,"position":10,"is_corresponding":false},{"id":1018098,"name":"Yong Tang","orcid":"0000-0002-3686-8990","position":11,"is_corresponding":false},{"id":684625,"name":"Utpal Das","orcid":"0000-0003-2239-7400","position":12,"is_corresponding":false},{"id":366302,"name":"David A. Scott","orcid":"0000-0003-1007-2756","position":13,"is_corresponding":false},{"id":232970,"name":"Padmini Rangamani","orcid":"0000-0001-5953-4347","position":14,"is_corresponding":false},{"id":824209,"name":"Yuki Ogawa","orcid":"0000-0003-2126-9087","position":15,"is_corresponding":false},{"id":562201,"name":"Subhojit Roy","orcid":"0000-0002-1571-2735","position":16,"is_corresponding":false},{"id":684624,"name":"Leonardo A Parra‐Rivas","orcid":"0000-0002-6707-1255","position":0,"is_corresponding":true}],"reference_count":107,"raw_metadata":null,"created_at":"2026-07-19T01:06:32.274501Z","pmid":"38128479","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}