{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:51:03Z","timestamp":1790725863765,"version":"4.1.0"},"posted":{"date-parts":[[2026,3,26]]},"group-title":"Genetics","reference-count":57,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R35NS137159"],"award-info":[{"award-number":["R35NS137159"]}]},{"name":"NIH","award":["U54NS123743"],"award-info":[{"award-number":["U54NS123743"]}]},{"name":"NIH","award":["R01AG064690"],"award-info":[{"award-number":["R01AG064690"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Frontotemporal dementia (FTD) is the second most common cause of dementia after Alzheimer disease. Mutations in\n                  <jats:italic>GRN<\/jats:italic>\n                  , which encodes progranulin, are a major cause of FTD. Common genetic variants in the\n                  <jats:italic>TMEM106B<\/jats:italic>\n                  gene modify risk of FTD and the effect is especially strong in\n                  <jats:italic>GRN<\/jats:italic>\n                  mutation carriers. Intriguingly, in\n                  <jats:italic>GRN<\/jats:italic>\n                  mutation carriers, being homozygous for the protective\n                  <jats:italic>TMEM106B<\/jats:italic>\n                  haplotype seems to confer near lifetime protection against FTD. Despite the strong genetic link between\n                  <jats:italic>GRN<\/jats:italic>\n                  and\n                  <jats:italic>TMEM106B<\/jats:italic>\n                  , how these two genes interact mechanistically has remained unresolved. Recent studies have revealed that a C-terminal fragment of TMEM106B forms amyloid fibrils and accumulates in the brains of older individuals and patients with neurodegenerative disorders, including FTD. How the production of this fragment connects to granulin deficiency is also unknown. Using lysosome immunoprecipitation, we show that granulin deficiency drives the accumulation of the TMEM106B C-terminal fragment within lysosomes in\n                  <jats:italic>Grn<\/jats:italic>\n                  -knockout mice and\n                  <jats:italic>GRN<\/jats:italic>\n                  -null human iPSC-derived neurons. Recombinant progranulin supplementation reduced TMEM106B C-terminal fragment accumulation. Isogenic neurons carrying the\n                  <jats:italic>TMEM106B<\/jats:italic>\n                  risk allele displayed allele-dose-dependent fragment accumulation that was reversible by progranulin. Structural and genetic analyses demonstrated that TMEM106B dimerization stabilizes the protein and limits C-terminal fragment formation. These findings define a lysosomal pathway linking granulin deficiency to TMEM106B C-terminal fragment accumulation and explain how protective\n                  <jats:italic>TMEM106B<\/jats:italic>\n                  alleles can confer resistance to FTD, even for\n                  <jats:italic>GRN<\/jats:italic>\n                  mutation carriers.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>\n                    Granulin deficiency drives lysosomal accumulation of an amyloidogenic TMEM106B C-terminal fragment, revealing a molecular mechanism that explains how\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    alleles can confer risk or protection from frontotemporal dementia.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.25.713523","type":"posted-content","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T05:25:38Z","timestamp":1774589138000},"source":"Crossref","is-referenced-by-count":3,"title":["Granulin loss and TMEM106B risk converge on lysosomal C-terminal fragment pathology in frontotemporal dementia"],"prefix":"10.64898","author":[{"given":"Yi","family":"Zeng","sequence":"first","affiliation":[{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA"},{"name":"The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Xiong","sequence":"additional","affiliation":[{"name":"The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, USA"},{"name":"Department of Chemical Engineering, Stanford University, Stanford, CA, USA"},{"name":"Stanford ChEM-H, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasiia","family":"Lovchykova","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thao Phuong","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Semma W.","family":"Gitler","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA"},{"name":"Northfield Mount Hermon School, Gill, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3772-0477","authenticated-orcid":false,"given":"Monther","family":"Abu-Remaileh","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA"},{"name":"The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, USA"},{"name":"Department of Chemical Engineering, Stanford University, Stanford, CA, USA"},{"name":"Stanford ChEM-H, Stanford University, Stanford, CA, USA"},{"name":"Arc Institute, Palo Alto, CA 94304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8603-1526","authenticated-orcid":false,"given":"Aaron D.","family":"Gitler","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA"},{"name":"The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, USA"},{"name":"Biohub \u2013 San Francisco; 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