{"doi":"10.1093/brain/awad032","title":"Tau–RNA complexes inhibit microtubule polymerization and drive disease-relevant conformation change","abstract":"Alzheimer's 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's 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's disease, progressive supranuclear palsy, corticobasal degeneration and Pick's 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.","journal":"Brain","year":2023,"id":323573,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":36,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9507,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1038833,"name":"Sarah J. Benbow","orcid":null,"position":1,"is_corresponding":false},{"id":531155,"name":"Rikki L. Uhrich","orcid":null,"position":2,"is_corresponding":false},{"id":351411,"name":"Aleen D. Saxton","orcid":"0000-0002-5055-5755","position":3,"is_corresponding":false},{"id":425512,"name":"Misa Baum","orcid":null,"position":4,"is_corresponding":false},{"id":363968,"name":"Timothy J. Strovas","orcid":"0000-0002-0176-0293","position":5,"is_corresponding":false},{"id":424780,"name":"Jeanna M. Wheeler","orcid":"0000-0003-1999-2225","position":6,"is_corresponding":false},{"id":472182,"name":"Jeremy D. Baker","orcid":null,"position":7,"is_corresponding":false},{"id":355965,"name":"Nicole F. Liachko","orcid":"0000-0003-1250-3871","position":8,"is_corresponding":false},{"id":38380,"name":"C. Dirk Keene","orcid":"0000-0002-5291-1469","position":9,"is_corresponding":false},{"id":363970,"name":"Caitlin S. Latimer","orcid":"0000-0003-3727-4278","position":10,"is_corresponding":false},{"id":351412,"name":"Brian C. Kraemer","orcid":"0000-0002-2252-7634","position":11,"is_corresponding":false},{"id":363969,"name":"Pamela J. McMillan","orcid":"0000-0003-1243-1951","position":0,"is_corresponding":true}],"reference_count":90,"raw_metadata":null,"created_at":"2026-07-19T01:07:52.377944Z","pmid":"36732296","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}