{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T06:14:40Z","timestamp":1791958480309,"version":"4.3.4"},"reference-count":89,"publisher":"Oxford University Press (OUP)","issue":"8","funder":[{"DOI":"10.13039\/100000738","name":"Department of Veterans Affairs","doi-asserted-by":"publisher","award":["#I01BX002619"],"award-info":[{"award-number":["#I01BX002619"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"Department of Veterans Affairs","doi-asserted-by":"publisher","award":["#I01BX004044"],"award-info":[{"award-number":["#I01BX004044"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["# RF1AG055474"],"award-info":[{"award-number":["# RF1AG055474"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["# R01NS064131"],"award-info":[{"award-number":["# R01NS064131"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG066729"],"award-info":[{"award-number":["R01AG066729"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K08 AG065426"],"award-info":[{"award-number":["K08 AG065426"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30 AG066509"],"award-info":[{"award-number":["P30 AG066509"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U19 AG066567"],"award-info":[{"award-number":["U19 AG066567"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007512","name":"Nancy and Buster Alvord endowment","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007512","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Alzheimer\u2019s disease and related disorders feature neurofibrillary tangles and other neuropathological lesions composed of detergent-insoluble tau protein. In recent structural biology studies of tau proteinopathy, aggregated tau forms a distinct set of conformational variants specific to the different types of tauopathy disorders. However, the constituents driving the formation of distinct pathological tau conformations on pathway to tau-mediated neurodegeneration remain unknown. Previous work demonstrated RNA can serve as a driver of tau aggregation, and RNA associates with tau containing lesions, but tools for evaluating tau\/RNA interactions remain limited. Here, we employed molecular interaction studies to measure the impact of tau\/RNA binding on tau microtubule binding and aggregation. To investigate the importance of tau\/RNA complexes (TRCs) in neurodegenerative disease, we raised a monoclonal antibody (TRC35) against aggregated tau\/RNA complexes. We showed that native tau binds RNA with high affinity but low specificity, and tau binding to RNA competes with tau-mediated microtubule assembly functions. Tau\/RNA interaction in vitro promotes the formation of higher molecular weight tau\/RNA complexes, which represent an oligomeric tau species. Coexpression of tau and poly(A)45 RNA transgenes in Caenorhabditis elegans exacerbates tau-related phenotypes including neuronal dysfunction and pathological tau accumulation. TRC35 exhibits specificity for Alzheimer\u2019s disease-derived detergent-insoluble tau relative to soluble recombinant tau. Immunostaining with TRC35 labels a wide variety of pathological tau lesions in animal models of tauopathy, which are reduced in mice lacking the RNA binding protein MSUT2. TRC-positive lesions are evident in many human tauopathies including Alzheimer\u2019s disease, progressive supranuclear palsy, corticobasal degeneration and Pick\u2019s disease. We also identified ocular pharyngeal muscular dystrophy as a novel tauopathy disorder, where loss of function in the poly(A) RNA binding protein (PABPN1) causes accumulation of pathological tau in tissue from post-mortem human brain. Tau\/RNA binding drives tau conformational change and aggregation inhibiting tau-mediated microtubule assembly. Our findings implicate cellular tau\/RNA interactions as modulators of both normal tau function and pathological tau toxicity in tauopathy disorders and suggest feasibility for novel therapeutic approaches targeting TRCs.<\/jats:p>","DOI":"10.1093\/brain\/awad032","type":"journal-article","created":{"date-parts":[[2023,1,28]],"date-time":"2023-01-28T01:11:55Z","timestamp":1674868315000},"page":"3206-3220","source":"Crossref","is-referenced-by-count":46,"title":["Tau\u2013RNA complexes inhibit microtubule polymerization and drive disease-relevant conformation change"],"prefix":"10.1093","volume":"146","author":[{"given":"Pamela J","family":"McMillan","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, University of Washington , Seattle, WA 98195 , USA"},{"name":"Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System , Seattle, WA 98108 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J","family":"Benbow","sequence":"additional","affiliation":[{"name":"Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System , Seattle, WA 98108 , USA"},{"name":"Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington , Seattle, WA 98104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rikki","family":"Uhrich","sequence":"additional","affiliation":[{"name":"Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System , Seattle, WA 98108 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleen","family":"Saxton","sequence":"additional","affiliation":[{"name":"Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System , Seattle, WA 98108 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misa","family":"Baum","sequence":"additional","affiliation":[{"name":"Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System , Seattle, WA 98108 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Strovas","sequence":"additional","affiliation":[{"name":"Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System , Seattle, WA 98108 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanna M","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System , Seattle, WA 98108 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Baker","sequence":"additional","affiliation":[{"name":"Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System , Seattle, WA 98108 , USA"},{"name":"Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington , Seattle, WA 98104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1250-3871","authenticated-orcid":false,"given":"Nicole F","family":"Liachko","sequence":"additional","affiliation":[{"name":"Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System , Seattle, WA 98108 , USA"},{"name":"Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington , Seattle, WA 98104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C Dirk","family":"Keene","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington , Seattle, WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin S","family":"Latimer","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington , Seattle, WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2252-7634","authenticated-orcid":false,"given":"Brian C","family":"Kraemer","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, University of Washington , Seattle, WA 98195 , USA"},{"name":"Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System , Seattle, WA 98108 , USA"},{"name":"Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington , Seattle, WA 98104 , USA"},{"name":"Department of Laboratory Medicine and Pathology, University of Washington , Seattle, WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,2,3]]},"reference":[{"key":"2023080207363593700_awad032-B1","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/S0197-4580(97)00054-7","article-title":"The natural history of Alzheimer neurofibrillary tangles and amyloid deposits","volume":"18","author":"Hyman","year":"1997","journal-title":"Neurobiol Aging"},{"key":"2023080207363593700_awad032-B2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/ana.410410106","article-title":"Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer\u2019s disease","volume":"41","author":"G\u00f3mez-Isla","year":"1997","journal-title":"Ann Neurol"},{"issue":"3 Pt 1","key":"2023080207363593700_awad032-B3","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1212\/WNL.42.3.631","article-title":"Neurofibrillary tangles but not senile plaques parallel duration and severity of 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Neuropathol"},{"key":"2023080207363593700_awad032-B23","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1002\/1531-8249(200007)48:1<77::AID-ANA12>3.0.CO;2-A","article-title":"Expression profile of transcripts in Alzheimer\u2019s disease tangle-bearing CA1 neurons","volume":"48","author":"Ginsberg","year":"2000","journal-title":"Ann Neurol"},{"key":"2023080207363593700_awad032-B24","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1016\/j.neuron.2021.03.026","article-title":"Tau aggregates are RNA\u2013protein assemblies that mislocalize multiple nuclear speckle components","volume":"109","author":"Lester","year":"2021","journal-title":"Neuron"},{"key":"2023080207363593700_awad032-B25","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/s40478-021-01219-1","article-title":"Pathological tau drives ectopic nuclear speckle scaffold protein SRRM2 accumulation in neuron cytoplasm in Alzheimer\u2019s 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