{"doi":"10.1101/2020.08.07.241471","title":"<i>Acat1</i> gene KO restores TGN cholesterol deficiency in mutant NPC1 cells and expands mutant <i>Npc1</i> mouse lifespan","abstract":"Abstract Niemann-Pick type C (NPC) is a neurological disorder with no cure. NPC proteins deliver cholesterol from endosomes to other compartments including trans-Golgi network (TGN) and endoplasmic reticulum (ER). Acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1) is a resident ER enzyme that converts cholesterol to cholesteryl esters for storage. Here, we report the surprising finding that in a mutant Npc1 mice, Acat1 -deficiency delayed the onset of weight loss and declining motor skill, prolonged lifespan, delayed Purkinje neuron death, and improved hepatosplenic pathology. Furthermore, syntaxin 6, a cholesterol-binding t-SNARE normally localized to TGN, is mislocalized in mutant NPC cells. However, upon ACAT1 inhibition this mislocalization is corrected, and increase the level of a few proteins further downstream. Our results imply that ACAT1 inhibition diverts a cholesterol storage pool in a way that replenished the low cholesterol level in NPC-deficient TGN. Taking together, we identify ACAT1 inhibition as a potential therapeutic target for NPC treatment.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":127182,"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":1,"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":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":294885,"name":"Catherine C.Y. Chang","orcid":"0000-0002-2187-8299","position":1,"is_corresponding":false},{"id":576502,"name":"Robert A. Maue","orcid":null,"position":2,"is_corresponding":false},{"id":506607,"name":"Elaina M. Melton","orcid":"0000-0002-4030-7766","position":3,"is_corresponding":false},{"id":575698,"name":"Andrew A. Peden","orcid":"0000-0003-0144-7712","position":4,"is_corresponding":false},{"id":471314,"name":"William S. Garver","orcid":"0000-0002-9635-8474","position":5,"is_corresponding":false},{"id":575699,"name":"Mitchell M. Huang","orcid":"0000-0002-5993-6415","position":6,"is_corresponding":false},{"id":576503,"name":"Peter W. Schroen","orcid":null,"position":7,"is_corresponding":false},{"id":294886,"name":"Ta‐Yuan Chang","orcid":"0000-0002-3249-0468","position":8,"is_corresponding":false},{"id":559216,"name":"Maximillian A. Rogers","orcid":"0000-0001-9277-3200","position":0,"is_corresponding":true}],"reference_count":107,"raw_metadata":null,"created_at":"2026-07-18T23:15:30.930746Z","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":[]}