{"doi":"10.1101/2024.04.18.590103","title":"SON-dependent nuclear speckle rehabilitation alleviates proteinopathies","abstract":"Current treatments targeting individual protein quality control pathways have limited efficacy in alleviating proteinopathies, highlighting the prerequisite for a common druggable target capable of global proteostasis modulation. Building upon our prior research establishing nuclear speckles as pivotal membrane-less organelles for transcriptional control of proteostasis, we aim to alleviate proteinopathies through nuclear speckle rehabilitation. We identified pyrvinium pamoate as a nuclear speckle rehabilitator that enhances protein quality control gene expression and suppresses YAP1 transcriptional activity via decreasing the surface/interfacial tension of nuclear speckle condensates through interaction with the intrinsically disordered region of nuclear speckle scaffold protein SON. In pre-clinical models, nanomolar pyrvinium pamoate protected against retinal degeneration and tauopathy mainly by promoting autophagy and ubiquitin-proteasome activity in a SON-dependent manner without causing stress. Aberrant nuclear speckle morphology, reduced protein quality control and increased YAP1 activity were observed in human tauopathies. Our study provides proof-of-principle of targeting nuclear speckles to ameliorate proteinopathies.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":486088,"datarank":0.25943335042599375,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.018017663560878677,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.018017663560878677,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":2,"citers_with_citation_signal":2,"citers_with_endowment":2,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.957,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1200713,"name":"Yuren Tao","orcid":null,"position":1,"is_corresponding":false},{"id":1329906,"name":"Maci Chambers","orcid":null,"position":2,"is_corresponding":false},{"id":1329544,"name":"Shanshan Zhao","orcid":"0000-0003-4083-1717","position":3,"is_corresponding":false},{"id":1279129,"name":"Riley K. 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