{"doi":"10.1101/2021.01.21.427704","title":"PIKfyve inhibition blocks endolysosomal escape of α-synuclein fibrils and spread of α-synuclein aggregation","abstract":"ABSTRACT The inter-cellular prion-like propagation of α-synuclein aggregation is emerging as an important mechanism driving the progression of neurodegenerative diseases including Parkinson’s disease and multiple system atrophy (MSA). To discover therapeutic strategies reducing the spread of α-synuclein aggregation, we performed a genome-wide CRISPR interference screen in a human cell-based model. We discovered that inhibiting PIKfyve dramatically reduced α-synuclein aggregation induced with both recombinant α-synuclein fibrils and fibrils isolated from MSA patient brain. While PIKfyve inhibition did not affect fibril uptake or α-synuclein clearance or secretion, it reduced α-synuclein trafficking from the early endosome to the lysosome, thereby limiting fibril escape from the lysosome and reducing the amount of fibrils that reach cytosolic α-synuclein to induce aggregation. These findings point to the endolysosomal transport of fibrils as a critical step in the propagation of α-synuclein aggregation and a potential therapeutic target.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":213478,"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":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9561,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":806076,"name":"Merissa Chen","orcid":null,"position":1,"is_corresponding":false},{"id":805511,"name":"Sophie Bax","orcid":"0009-0001-7820-2716","position":2,"is_corresponding":false},{"id":218679,"name":"Ruilin Tian","orcid":"0000-0001-7680-6682","position":3,"is_corresponding":false},{"id":471322,"name":"Amanda L. Woerman","orcid":"0000-0003-4029-1968","position":4,"is_corresponding":false},{"id":227715,"name":"Eric Tse","orcid":"0000-0002-2082-9006","position":5,"is_corresponding":false},{"id":256136,"name":"Isabel Johnson","orcid":"0000-0002-3294-4423","position":6,"is_corresponding":false},{"id":108132,"name":"Carlos Nowotny","orcid":"0000-0002-1260-0279","position":7,"is_corresponding":false},{"id":805512,"name":"Elise N. Muñoz","orcid":"0000-0003-4341-8119","position":8,"is_corresponding":false},{"id":805513,"name":"Janine Sengstack","orcid":"0000-0002-2167-494X","position":9,"is_corresponding":false},{"id":565763,"name":"Daniel R. Southworth","orcid":"0000-0001-7108-9389","position":10,"is_corresponding":false},{"id":275686,"name":"Jason E. Gestwicki","orcid":"0000-0002-6125-3154","position":11,"is_corresponding":false},{"id":109264,"name":"Manuel D. Leonetti","orcid":"0000-0002-4881-405X","position":12,"is_corresponding":false},{"id":218683,"name":"Martin Kampmann","orcid":"0000-0002-3819-7019","position":13,"is_corresponding":false},{"id":806075,"name":"Stephanie K. See","orcid":null,"position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-18T23:52:36.886828Z","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":[]}