{"doi":"10.1016/j.jbc.2022.102571","title":"Aging-associated REGγ proteasome decline predisposes to tauopathy","abstract":"The REGγ-20S proteasome is an ubiquitin- and ATP-independent degradation system, targeting selective substrates, possibly helping to regulate aging. The studies we report here demonstrate that aging-associated REGγ decline predisposes to decreasing tau turnover, as in a tauopathy. The REGγ proteasome promotes degradation of human and mouse tau, notably phosphorylated tau and toxic tau oligomers that shuttle between the cytoplasm and nuclei. REGγ-mediated proteasomal degradation of tau was validated in 3- to 12-month-old REGγ KO mice, REGγ KO;PS19 mice, and PS19 mice with forebrain conditional neuron-specific overexpression of REGγ (REGγ OE) and behavioral abnormalities. Coupled with tau accumulation, we found with REGγ-deficiency, neuron loss, dendrite reduction, tau filament accumulation, and microglial activation are much more prominent in the REGγ KO;PS19 than the PS19 model. Moreover, we observed that the degenerative neuronal lesions and aberrant behaviors were alleviated in REGγ OE;PS19 mice. Memory and other behavior analysis substantiate the role of REGγ in prevention of tauopathy-like symptoms. In addition, we investigated the potential mechanism underlying aging-related REGγ decline. This study provides valuable insights into the novel regulatory mechanisms and potential therapeutic targets for tau-related neurodegenerative diseases.","journal":"Journal of Biological Chemistry","year":2022,"id":275808,"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":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9479,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":945378,"name":"Haiyang Zhang","orcid":"0000-0002-2410-7078","position":1,"is_corresponding":false},{"id":945379,"name":"Ting Yang","orcid":"0000-0002-8182-0195","position":2,"is_corresponding":false},{"id":98679,"name":"Yun Liu","orcid":"0000-0003-4377-1211","position":3,"is_corresponding":false},{"id":945848,"name":"Solomon Kibreab","orcid":null,"position":4,"is_corresponding":false},{"id":945380,"name":"Yunpeng Zhang","orcid":"0000-0001-5144-3803","position":5,"is_corresponding":false},{"id":945381,"name":"Liangcai Gao","orcid":"0000-0001-9444-1568","position":6,"is_corresponding":false},{"id":410668,"name":"Robb E. Moses","orcid":null,"position":7,"is_corresponding":false},{"id":304057,"name":"Bert W. O’Malley","orcid":"0000-0003-3332-1399","position":8,"is_corresponding":false},{"id":885692,"name":"Jianru Xiao","orcid":"0000-0003-0259-9523","position":9,"is_corresponding":false},{"id":409795,"name":"Xiaotao Li","orcid":"0000-0002-6119-1344","position":10,"is_corresponding":false},{"id":945377,"name":"Jialu Tu","orcid":"0000-0003-2728-7200","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T00:28:21.971703Z","pmid":"36209822","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":[]}