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We treated human neurons and neuron-like cells with 30 postmortem brain samples and quantified neoaggregate formation, loss of function and changes in the TDP-43 interactome to define determinants of seeding outcomes. Potent FTLD-TDP-A seeds drove a progressive collapse of physiological TDP-43 interactions accompanied by functional loss. Beyond the burden of pathological TDP-43, we identified the fibrillar core of the lysosomal protein TMEM106B as a critical pro-seeding factor. Transient lysosomal injury markedly enhanced neoaggregation and loss of function, likely by promoting fibril interactions with native TDP-43. Our work establishes a mechanistic link between TMEM106B and TDP-43 aggregation, identifies lysosomal escape as a key driver of pathology and introduces the strongest model yet for seeded TDP-43 aggregation and loss of function, to enable discovery of disease modifiers.<\/jats:p>","DOI":"10.64898\/2025.12.19.695531","type":"posted-content","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T01:50:13Z","timestamp":1766454613000},"source":"Crossref","is-referenced-by-count":5,"title":["Lysosomal escape and TMEM106B fibrillar core determine TDP-43 seeding outcomes"],"prefix":"10.64898","author":[{"given":"Weijia","family":"Zhong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Scial\u00f2","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Gatta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon","family":"H\u00e4fliger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noemi","family":"Leu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavio","family":"Lurati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Peter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nandini","family":"Ramesh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Roschitzki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Somanath","family":"Jagannath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruchi","family":"Manglunia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"de Cecco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su Min","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar G","family":"Wilkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0344-6708","authenticated-orcid":false,"given":"Adriano","family":"Aguzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5296-8051","authenticated-orcid":false,"given":"Michael","family":"Ward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7554-1632","authenticated-orcid":false,"given":"Pietro","family":"Fratta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard","family":"Petrucelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clotilde","family":"Lagier-Tourenne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1271-9445","authenticated-orcid":false,"given":"Magdalini","family":"Polymenidou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025122409350683000_2025.12.19.695531v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.10.093"},{"key":"2025122409350683000_2025.12.19.695531v1.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1134108"},{"key":"2025122409350683000_2025.12.19.695531v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.07.033"},{"key":"2025122409350683000_2025.12.19.695531v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04436-3"},{"key":"2025122409350683000_2025.12.19.695531v1.5","doi-asserted-by":"crossref","unstructured":"De Rossi, P. , A.J. 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