{"doi":"10.1371/journal.pbio.3001287","title":"α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes","abstract":"The accumulation of α-synuclein (α-syn) aggregates in specific brain regions is a hallmark of synucleinopathies including Parkinson disease (PD). α-Syn aggregates propagate in a \"prion-like\" manner and can be transferred inside lysosomes to recipient cells through tunneling nanotubes (TNTs). However, how lysosomes participate in the spreading of α-syn aggregates is unclear. Here, by using super-resolution (SR) and electron microscopy (EM), we find that α-syn fibrils affect the morphology of lysosomes and impair their function in neuronal cells. In addition, we demonstrate that α-syn fibrils induce peripheral redistribution of lysosomes, likely mediated by transcription factor EB (TFEB), increasing the efficiency of α-syn fibrils' transfer to neighboring cells. We also show that lysosomal membrane permeabilization (LMP) allows the seeding of soluble α-syn in cells that have taken up α-syn fibrils from the culture medium, and, more importantly, in healthy cells in coculture, following lysosome-mediated transfer of the fibrils. Moreover, we demonstrate that seeding occurs mainly at lysosomes in both donor and acceptor cells, after uptake of α-syn fibrils from the medium and following their transfer, respectively. Finally, by using a heterotypic coculture system, we determine the origin and nature of the lysosomes transferred between cells, and we show that donor cells bearing α-syn fibrils transfer damaged lysosomes to acceptor cells, while also receiving healthy lysosomes from them. These findings thus contribute to the elucidation of the mechanism by which α-syn fibrils spread through TNTs, while also revealing the crucial role of lysosomes, working as a Trojan horse for both seeding and propagation of disease pathology.","journal":"PLoS Biology","year":2021,"id":148608,"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":123,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9578,"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":632340,"name":"Maura Samarani","orcid":"0000-0002-6376-5524","position":1,"is_corresponding":false},{"id":633523,"name":"Sylvie Syan","orcid":null,"position":2,"is_corresponding":false},{"id":251543,"name":"Carlos M. Guardia","orcid":"0000-0002-4662-9360","position":3,"is_corresponding":false},{"id":632341,"name":"Takashi Nonaka","orcid":"0000-0002-0830-9403","position":4,"is_corresponding":false},{"id":560409,"name":"Nalan Liv","orcid":"0000-0003-2654-9117","position":5,"is_corresponding":false},{"id":633524,"name":"Patricia Latour‐Lambert","orcid":null,"position":6,"is_corresponding":false},{"id":614850,"name":"Masato Hasegawa","orcid":"0000-0001-7415-8159","position":7,"is_corresponding":false},{"id":560410,"name":"Judith Klumperman","orcid":"0000-0003-4835-6228","position":8,"is_corresponding":false},{"id":62801,"name":"Juan S. Bonifacino","orcid":"0000-0002-5673-6370","position":9,"is_corresponding":false},{"id":632342,"name":"Chiara Zurzolo","orcid":"0000-0001-6048-6602","position":10,"is_corresponding":false},{"id":633522,"name":"Aysegul Dilsizoglu Senol","orcid":null,"position":0,"is_corresponding":true}],"reference_count":147,"raw_metadata":null,"created_at":"2026-07-18T23:42:46.224799Z","pmid":"34283825","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":[]}