{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:50:59Z","timestamp":1790725859055,"version":"4.1.0"},"posted":{"date-parts":[[2026,3,28]]},"group-title":"Cell Biology","reference-count":125,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T00:00:00Z","timestamp":1774656000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,28]]},"abstract":"<jats:p>\n                  Variants in\n                  <jats:italic>TMEM106B<\/jats:italic>\n                  and\n                  <jats:italic>GRN<\/jats:italic>\n                  , which encode lysosomal proteins, interact through unknown mechanisms to increase the risk of age-related cognitive decline and neurodegeneration. Here, we show that these variants converge on a single molecular intermediate: the cleaved intra-lysosomal fibril core of TMEM106B, a precursor to amyloid fibrils that accumulate in the aging brain. A protein-coding\n                  <jats:italic>TMEM106B<\/jats:italic>\n                  risk variant (p.T185) drives fibril core accumulation by impairing its degradation and\n                  <jats:italic>GRN<\/jats:italic>\n                  risk variants amplify this effect. Mice over-expressing the fibril core develop hallmarks of neurodegeneration, and cryo-electron tomography reveals intra-lysosomal fibrils in cultured neurons, mice, and diseased human brain. In\n                  <jats:italic>GRN<\/jats:italic>\n                  -mutation carriers, in whom fibril burden is greatest, fibrils extrude through ruptured lysosomal membranes. These findings identify intra-lysosomal TMEM106B fibrillization as a convergent neurodegeneration mechanism and potential therapeutic target.\n                <\/jats:p>","DOI":"10.64898\/2026.03.26.714634","type":"posted-content","created":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T18:10:18Z","timestamp":1774721418000},"source":"Crossref","is-referenced-by-count":4,"title":["Neurodegeneration risk variants promote lysosomal TMEM106B fibril accumulation"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2735-8195","authenticated-orcid":false,"given":"John Michael","family":"Replogle","sequence":"first","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan D.","family":"Marks","sequence":"additional","affiliation":[{"name":"Medical Scientist Training Program, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA"},{"name":"Neuroscience Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2598-9682","authenticated-orcid":false,"given":"Martin G.","family":"Fernandez","sequence":"additional","affiliation":[{"name":"Department of Biophysics, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hebao","family":"Yuan","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dahyun","family":"Yu","sequence":"additional","affiliation":[{"name":"Neuroscience Graduate Program, Mayo Graduate School, Mayo Clinic College of 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