{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T02:11:40Z","timestamp":1780452700876,"version":"3.54.1"},"reference-count":111,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,3,29]],"date-time":"2024-03-29T00:00:00Z","timestamp":1711670400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Campus Guadalajara","award":["1097536"],"award-info":[{"award-number":["1097536"]}]},{"name":"PROSNI (support program to improve the production conditions of research members) from Universidad de Guadalajara","award":["1097536"],"award-info":[{"award-number":["1097536"]}]},{"name":"CONACYT-Mexico","award":["1097536"],"award-info":[{"award-number":["1097536"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Niemann\u2013Pick Type C (NPC) represents an autosomal recessive disorder with an incidence rate of 1 in 150,000 live births, classified within lysosomal storage diseases (LSDs). The abnormal accumulation of unesterified cholesterol characterizes the pathophysiology of NPC. This phenomenon is not unique to NPC, as analogous accumulations have also been observed in Alzheimer\u2019s disease, Parkinson\u2019s disease, and other neurodegenerative disorders. Interestingly, disturbances in the folding of the mutant protein NPC1 I1061T are accompanied by the aggregation of proteins such as hyperphosphorylated tau, \u03b1-synuclein, TDP-43, and \u03b2-amyloid peptide. These accumulations suggest potential disruptions in proteostasis, a regulatory process encompassing four principal mechanisms: synthesis, folding, maintenance of folding, and protein degradation. The dysregulation of these processes leads to excessive accumulation of abnormal proteins that impair cell function and trigger cytotoxicity. This comprehensive review delineates reported alterations across proteostasis mechanisms in NPC, encompassing changes in processes from synthesis to degradation. Additionally, it discusses therapeutic interventions targeting pharmacological facets of proteostasis in NPC. Noteworthy among these interventions is valproic acid, a histone deacetylase inhibitor (HDACi) that modulates acetylation during NPC1 synthesis. In addition, various therapeutic options addressing protein folding modulation, such as abiraterone acetate, DHBP, calnexin, and arimoclomol, are examined. Additionally, treatments impeding NPC1 degradation, exemplified by bortezomib and MG132, are explored as potential strategies. This review consolidates current knowledge on proteostasis dysregulation in NPC and underscores the therapeutic landscape targeting diverse facets of this intricate process.<\/jats:p>","DOI":"10.3390\/ijms25073806","type":"journal-article","created":{"date-parts":[[2024,4,4]],"date-time":"2024-04-04T11:11:09Z","timestamp":1712229069000},"page":"3806","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Alterations in Proteostasis Mechanisms in Niemann\u2013Pick Type C Disease"],"prefix":"10.3390","volume":"25","author":[{"given":"Iris Valeria","family":"Serv\u00edn Mu\u00f1oz","sequence":"first","affiliation":[{"name":"Laboratorio de Neuroinmunobiolog\u00eda Molecular, Instituto de Investigaci\u00f3n en Ciencias Biom\u00e9dicas (IICB), Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7443-2514","authenticated-orcid":false,"given":"Daniel","family":"Ortu\u00f1o-Sahag\u00fan","sequence":"additional","affiliation":[{"name":"Laboratorio de Neuroinmunobiolog\u00eda Molecular, Instituto de Investigaci\u00f3n en Ciencias Biom\u00e9dicas (IICB), Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5424-9130","authenticated-orcid":false,"given":"Christian","family":"Gri\u00f1\u00e1n-Ferr\u00e9","sequence":"additional","affiliation":[{"name":"Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, Universitat de Barcelona, 08028 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red (CiberNed), Network Center for Neurodegenerative Diseases, National Spanish Health Institute Carlos III, 28220 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3095-4254","authenticated-orcid":false,"given":"Merc\u00e8","family":"Pall\u00e0s","sequence":"additional","affiliation":[{"name":"Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, Universitat de Barcelona, 08028 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red (CiberNed), Network Center for Neurodegenerative Diseases, National Spanish Health Institute Carlos III, 28220 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia","family":"Gonz\u00e1lez-Castillo","sequence":"additional","affiliation":[{"name":"Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Campus Guadalajara, Zapopan 45201, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1083\/jcb.201709072","article-title":"Pathways of cellular proteostasis in aging and disease","volume":"217","author":"Klaips","year":"2018","journal-title":"J. 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