{"doi":"10.1101/183723","title":"Chaperone AMPylation modulates aggregation and toxicity of neurodegenerative disease-associated polypeptides","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Proteostasis is critical to maintain organismal viability, a process counteracted by aging-dependent protein aggregation. Chaperones of the heat shock protein (HSP) family help control proteostasis by reducing the burden of unfolded proteins. They also oversee the formation of protein aggregates. Here, we explore how AMPylation – a post-translational protein modification that has emerged as a powerful modulator of HSP70 activity – influences the dynamics of protein aggregation. We find that adjustments of cellular AMPylation levels in\n                  <jats:italic>C.elegans</jats:italic>\n                  directly affect aggregation properties and associated toxicity of amyloid-β (Aβ), of a polyglutamine (polyQ)- extended polypeptide and of α-synuclein (α-syn). Expression of a constitutively active\n                  <jats:italic>C. elegans</jats:italic>\n                  AMPylase Fic-1(E274G) under its own promoter expedites aggregation of Aβ and α-syn, and drastically reduces their toxicity. A deficiency in AMPylation decreases the cellular tolerance for aggregation-prone polyQ proteins and alters their aggregation behavior. Over-expression of Fic-1(E274G) interferes with cell survival and larval development, underscoring the need for tight control of AMPylase activity\n                  <jats:italic>in vivo</jats:italic>\n                  . We thus define a link between HSP70 AMPylation and the dynamics of protein aggregation in neurodegenerative disease models. Our results are consistent with a cyto-protective, rather than a cytotoxic role for such protein aggregates.\n                </jats:p>","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":null,"id":22643,"datarank":0.19627041761563846,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.03147857431542199,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.03147857431542199,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":2,"citers_with_citation_signal":2,"citers_with_endowment":2,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":141678,"name":"David Pincus","orcid":"0000-0002-9651-6858","position":1,"is_corresponding":false},{"id":141679,"name":"Hidde L. Ploegh","orcid":null,"position":2,"is_corresponding":false},{"id":141677,"name":"Matthias C. Truttmann","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"21071399","pmcid":null,"openalex_id":"https://openalex.org/W2950766996","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"4DP5OD017941-04","title":"Quantitative approaches to reveal the homeostatic control mechanisms of stress re"}],"total_grants":1,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2021,"count":1},{"year":2022,"count":1}],"oa_status":"green","license":"CC BY NC ND","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2017/09/01/183723.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2017/09/01/183723.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/183723","host_type":"publisher"},{"url":"https://doi.org/10.1101/183723","host_type":"repository"},{"url":"https://doi.org/10.1073/pnas.1801989115","host_type":""},{"url":"https://www.pnas.org/content/pnas/115/22/E5008.full.pdf","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/29760078","host_type":""},{"url":"http://dx.doi.org/10.1073/pnas.1801989115","host_type":""},{"url":"https://dx.doi.org/10.1073/pnas.1801989115","host_type":""},{"url":"https://dx.doi.org/10.1101/183723","host_type":""},{"url":"http://dx.doi.org/10.1101/183723","host_type":""}],"fields_of_study":["Genetics, Aging, and Longevity in Model Organisms","Heat shock proteins research","Endoplasmic Reticulum Stress and Disease","0301 basic medicine","03 medical and health sciences"],"mesh_terms":[],"keywords":["Proteostasis","Protein aggregation","Chaperone (clinical)","Cell biology","Hsp70","Heat shock protein","Protein folding","Chemistry","Toxicity","Amyloid (mycology)","Adenylylation","Biology","Biochemistry","Enzyme","Gene","Amyloid","Amyloid beta-Peptides","Neurodegenerative Diseases","Nucleotidyltransferases","Protein Aggregation, Pathological","Adenosine Monophosphate","PNAS Plus","alpha-Synuclein","Animals","HSP70 Heat-Shock Proteins","Caenorhabditis elegans","Caenorhabditis elegans Proteins","Peptides","Protein Processing, Post-Translational","Molecular Chaperones"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-07T14:55:03.228437Z","pmid":null,"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":[]}