{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T08:26:28Z","timestamp":1762503988594},"reference-count":29,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2014,8,21]],"date-time":"2014-08-21T00:00:00Z","timestamp":1408579200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2014,10]]},"abstract":"<jats:sec><jats:label \/><jats:p>Niemann\u2013Pick disease type C (<jats:styled-content style=\"fixed-case\">NPC<\/jats:styled-content>) is a lipid storage disorder mainly caused by mutations in the <jats:italic><jats:styled-content style=\"fixed-case\">NPC<\/jats:styled-content>1<\/jats:italic> gene. Approximately 60% of these mutations are missense changes that may induce reduced <jats:styled-content style=\"fixed-case\">NPC<\/jats:styled-content>1 protein levels by increased degradation via ubiquitin\u2013proteasome. This is the case for the most prevalent worldwide mutation, p.Ile1061Thr, as well as for other three missense changes. In the present study, we analyzed the <jats:styled-content style=\"fixed-case\">NPC<\/jats:styled-content>1 levels in fibroblasts from eighteen <jats:styled-content style=\"fixed-case\">NPC<\/jats:styled-content> patients presenting missense mutations. We found that fourteen of these cells lines showed decreased levels of <jats:styled-content style=\"fixed-case\">NPC<\/jats:styled-content>1. Six of these cell lines were homozygous, whereas the other eight were associated with a frame shifting mutation. We focused our attention in the NPC homozygous samples and demonstrated that, in most of the cases, <jats:styled-content style=\"fixed-case\">NPC<\/jats:styled-content>1 reduction was a consequence of a decrease of its half\u2010life. <jats:styled-content style=\"fixed-case\">NPC<\/jats:styled-content> cells were treated not only with the proteasome inhibitors carbobenzoxy\u2010<jats:sc>l<\/jats:sc>\u2010leucyl\u2010<jats:sc>l<\/jats:sc>\u2010leucyl\u2010<jats:sc>l<\/jats:sc>\u2010leucinal or <jats:italic>N<\/jats:italic>\u2010acetyl\u2010leucyl\u2010leucyl\u2010norleucinal, both widely used as a research tools, but also with bortezomib, the first proteasome inhibitor to reach clinical applications, although it has never been used in <jats:styled-content style=\"fixed-case\">NPC<\/jats:styled-content> disease. We observed that, after treatment, the mutant <jats:styled-content style=\"fixed-case\">NPC<\/jats:styled-content>1 protein levels were partially recovered in most of the cell lines. Importantly, these mutant proteins partially recovered their activity and substantially reduced free cholesterol levels. These results suggest that by enhancing the <jats:styled-content style=\"fixed-case\">NPC<\/jats:styled-content>1 protein stability with the use of proteasome inhibitors, their functionality might be recovered and this might represent a therapeutical approach for future treatments of <jats:styled-content style=\"fixed-case\">NPC<\/jats:styled-content> disease resulting from specific missense mutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Database<\/jats:title><jats:p>Nucleotide and protein sequence data are available in the Genbank database under the accession numbers <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.ncbi.nlm.nih.gov\/protein\/NM_000271.3\">NM_000271.3<\/jats:ext-link> and <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.ncbi.nlm.nih.gov\/protein\/NP_000262.1\">NP_000262.1<\/jats:ext-link>, respectively. Functional protein information is available in the UniProt protein database under the accession number <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.uniprot.org\/uniprot\/O15118\">O15118<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/febs.12954","type":"journal-article","created":{"date-parts":[[2014,8,5]],"date-time":"2014-08-05T12:01:32Z","timestamp":1407240092000},"page":"4450-4466","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["The proteasome inhibitor bortezomib reduced cholesterol accumulation in fibroblasts from Niemann\u2013Pick type C patients carrying missense mutations"],"prefix":"10.1111","volume":"281","author":[{"given":"Judit","family":"Mac\u00edas\u2010Vidal","sequence":"first","affiliation":[{"name":"Secci\u00f3 d'Errors Cong\u00e8nits del Metabolisme (IBC) Servei de Bioqu\u00edmica i Gen\u00e8tica Molecular Hospital Cl\u00ednic Barcelona 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