{"doi":"10.1101/2023.08.25.554320","title":"S-Nitrosylation of CRTC1 in Alzheimer’s disease impairs CREB-dependent gene expression induced by neuronal activity","abstract":"SUMMARY CREB-regulated transcription coactivator 1 (CRTC1) plays an important role in synaptic plasticity, learning and long-term memory formation through regulation of neuronal activity-dependent gene expression, and CRTC1 dysregulation is implicated in Alzheimer’s disease (AD). Here, we show that increased S-nitrosylation of CRTC1 (forming SNO-CRTC1), as seen in cell-based, animal-based, and human induced pluripotent stem cell (hiPSC)-derived cerebrocortical neuron-based AD models, disrupts its binding with CREB and diminishes the activity-dependent gene expression mediated by the CRTC1/CREB pathway. We identified Cys216 of CRTC1 as the primary target of S-nitrosylation by nitric oxide (NO)-related species. Using CRISPR/Cas9 techniques, we mutated Cys216 to Ala in hiPSC-derived cerebrocortical neurons bearing one allele of the APP Swe mutation (AD-hiPSC neurons). Introduction of this non-nitrosylatable CRTC1 construct rescued defects in AD-hiPSC neurons, including decreased neurite length and increased neuronal cell death. Additionally, expression of non-nitrosylatable CRTC1 in vivo in the hippocampus rescued synaptic plasticity in the form of long-term potentiation (LTP) in 5XFAD mice. Taken together, these results demonstrate that formation of SNO-CRTC1 contributes to the pathogenesis of AD by attenuating the neuronal activity-dependent CREB transcriptional pathway, and suggests a novel therapeutic target for AD.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":397149,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"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":262441,"name":"Roman Vlkolinský","orcid":"0000-0002-9786-0407","position":1,"is_corresponding":false},{"id":1172747,"name":"Chongyang Wu","orcid":"0009-0005-5504-3627","position":2,"is_corresponding":false},{"id":300266,"name":"Nima Dolatabadi","orcid":null,"position":3,"is_corresponding":false},{"id":298841,"name":"Henry Scott","orcid":"0000-0002-4462-8479","position":4,"is_corresponding":false},{"id":647841,"name":"Olga Prikhodko","orcid":"0000-0001-9846-1574","position":5,"is_corresponding":false},{"id":1173095,"name":"Mayra Blanco","orcid":null,"position":6,"is_corresponding":false},{"id":322761,"name":"Nhi Lang","orcid":"0000-0001-7187-1194","position":7,"is_corresponding":false},{"id":636563,"name":"Juan Piña-Crespo","orcid":"0000-0003-2803-7377","position":8,"is_corresponding":false},{"id":298845,"name":"Tomohiro Nakamura","orcid":"0000-0002-4246-7771","position":9,"is_corresponding":false},{"id":262444,"name":"Marisa Roberto","orcid":"0000-0003-0729-3961","position":10,"is_corresponding":false},{"id":292124,"name":"Stuart A. Lipton","orcid":"0000-0002-3490-1259","position":11,"is_corresponding":false},{"id":555431,"name":"Xu Zhang","orcid":"0000-0001-6075-6000","position":0,"is_corresponding":true}],"reference_count":83,"raw_metadata":null,"created_at":"2026-07-19T01:19:35.497854Z","pmid":null,"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":[]}