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Adv."],"published-print":{"date-parts":[[2026,1,30]]},"abstract":"<jats:p>\n                    Alzheimer\u2019s disease (AD) risk is strongly influenced by genetic variants that converge on pathways regulating endosomal homeostasis. Among these,\n                    <jats:italic toggle=\"yes\">BIN1<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">RIN3<\/jats:italic>\n                    have emerged as susceptibility genes, yet their functional relationship in AD remains largely unknown. Here, we investigated how BIN1 and RIN3 interaction regulates RAB5 activity and endosomal pathology. RIN3 has been shown to bind BIN1, and we previously reported that this interaction modulates amyloid-\u03b2 (A\u03b2) precursor protein (APP) trafficking and A\u03b2 generation in vitro. To extend these findings, we used\n                    <jats:italic toggle=\"yes\">Rin3<\/jats:italic>\n                    constitutive knockout (\n                    <jats:italic toggle=\"yes\">Rin3-CKO<\/jats:italic>\n                    ) mice and CRISPR-Cas9\u2013edited human induced pluripotent stem cell\u2013derived neurons carrying either\n                    <jats:italic toggle=\"yes\">BIN1<\/jats:italic>\n                    knockout or rare familial AD\n                    <jats:italic toggle=\"yes\">RIN3<\/jats:italic>\n                    missense mutations within the BIN1-binding domain. We found that disruption of BIN1-RIN3 binding, through either genetic deletion or pathogenic RIN3 variants, resulted in RIN3-mediated RAB5 hyperactivation and enlargement of neuronal endosomes, a hallmark of early AD pathology. Transcriptomic profiling further revealed dysregulated expression of AD-related genes. Together, these findings establish BIN1 as a critical regulator of RIN3-driven RAB5 activation and neuronal endosomal homeostasis.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adx2127","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T18:59:52Z","timestamp":1769626792000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["<i>RIN3<\/i>\n                    mutations impairing binding of the Alzheimer\u2019s disease\u2013associated protein BIN1 lead to RAB5 hyperactivation and endosomal pathology"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9440-0712","authenticated-orcid":true,"given":"Anna K.","family":"Maaser-Hecker","sequence":"first","affiliation":[{"name":"Genetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob C.","family":"Zellmer","sequence":"additional","affiliation":[{"name":"Genetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Kim","sequence":"additional","affiliation":[{"name":"Genetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grisilda","family":"Bakiasi","sequence":"additional","affiliation":[{"name":"Genetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4918-3592","authenticated-orcid":true,"given":"Amit K.","family":"Maiti","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomics, Mydnavar, 28475 Greenfield Rd. STE 113 PMB 52423, Southfield, MI 48076, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matea P. C.","family":"Curtat","sequence":"additional","affiliation":[{"name":"Genetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7905-4380","authenticated-orcid":true,"given":"Se Hoon","family":"Choi","sequence":"additional","affiliation":[{"name":"Genetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1844-5652","authenticated-orcid":true,"given":"Dmitry","family":"Prokopenko","sequence":"additional","affiliation":[{"name":"Genetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7032-1454","authenticated-orcid":true,"given":"Rudolph E.","family":"Tanzi","sequence":"additional","affiliation":[{"name":"Genetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9754-3380","authenticated-orcid":true,"given":"Raja","family":"Bhattacharyya","sequence":"additional","affiliation":[{"name":"Genetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology, MassGeneral Institute for 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