{"doi":"10.1016/j.celrep.2023.112838","title":"Increased degradation of FMRP contributes to neuronal hyperexcitability in tuberous sclerosis complex","abstract":"Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder, but new therapies have been impeded by a lack of understanding of the pathological mechanisms. Tuberous sclerosis complex (TSC) and fragile X syndrome are associated with alterations in the mechanistic target of rapamycin (mTOR) and fragile X messenger ribonucleoprotein 1 (FMRP), which have been implicated in the development of ASD. Previously, we observed that transcripts associated with FMRP were down-regulated in TSC2-deficient neurons. In this study, we find that FMRP turnover is dysregulated in TSC2-deficient rodent primary neurons and human induced pluripotent stem cell (iPSC)-derived neurons and is dependent on the E3 ubiquitin ligase anaphase-promoting complex. We also demonstrate that overexpression of FMRP can partially rescue hyperexcitability in TSC2-deficient iPSC-derived neurons. These data indicate that FMRP dysregulation represents an important pathological mechanism in the development of abnormal neuronal activity in TSC and illustrate a molecular convergence between these two neurogenetic disorders.","journal":"Cell Reports","year":2023,"id":343039,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9509,"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":1080511,"name":"Truc Pham","orcid":null,"position":1,"is_corresponding":false},{"id":1065741,"name":"Nicole A. Teaney","orcid":"0009-0007-9069-4606","position":2,"is_corresponding":false},{"id":1080512,"name":"Juan Pablo Ruíz","orcid":null,"position":3,"is_corresponding":false},{"id":745212,"name":"Ryan Chen","orcid":"0000-0003-0027-483X","position":4,"is_corresponding":false},{"id":1065743,"name":"Cidi Chen","orcid":"0000-0001-7112-2230","position":5,"is_corresponding":false},{"id":40873,"name":"Mustafa Şahin","orcid":"0000-0002-3490-6009","position":6,"is_corresponding":false},{"id":497313,"name":"Kellen D. Winden","orcid":"0000-0001-5816-3724","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-19T01:11:17.288563Z","pmid":"37494191","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":[]}