Roles of the ubiquitin peptidase USP18 in multiple sclerosis and the response to interferon‐β treatment. Issue 10 (22nd May 2013)

• Record Type: Journal Article
• Authors: Malhotra, S.; Morcillo‐Suárez, C.; Nurtdinov, R.; Rio, J.; Sarro, E.; Moreno, M.; Castilló, J.; Navarro, A.; Montalban, X.; Comabella, M.
• Is Part Of: European journal of neurology. Volume 20:Issue 10(2013:Oct.)
• Page Start: 1390
• Page End: 1397
• Publication Date: 2013-05-22
• Subjects: Neurology -- Periodicals; Nervous system -- Diseases -- Periodicals; 616.8
• DOI: 10.1111/ene.12193
• Languages: English
• ISSNs: 1351-5101

Abstract

<abstract abstract-type="main" id="ene12193-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ene12193-sec-0001" sec-type="section"> <title>Background and purpose</title> <p>Ubiquitin specific peptidase 18 (<italic>USP18</italic>) is a deubiquitinating enzyme that functions as a negative regulator of the type I interferon (IFN) signalling pathway and is specifically induced by type I IFNs. In the present study, previous observations by our group were expanded suggesting an implication of <italic>USP18</italic> in multiple sclerosis (MS) based on the finding of a deficient expression of the gene in peripheral blood mononuclear cells from MS patients compared with healthy controls.</p> </sec> <sec id="ene12193-sec-0002" sec-type="section"> <title>Methods</title> <p>Two polymorphisms, rs2542109 (intronic) and rs9618216 (promoter), were genotyped in a cohort of 691 relapse‐onset MS patients and 1028 healthy controls and in 225 MS patients treated with IFNβ and classified into responders and non‐responders after 2 years of treatment according to clinical criteria. Correlations between genotypes and expression levels for <italic>USP18</italic> and its target <italic>ISG15</italic> were performed by real‐time polymerase chain reaction.</p> </sec> <sec id="ene12193-sec-0003" sec-type="section"> <title>Results</title> <p>Two <italic>USP18</italic> haplotypes were significantly associated with MS, <italic> TG</italic> and <italic>CG</italic>. Additional experiments revealed that <italic>CG</italic> carriers were characterized by lower <italic>USP18</italic> gene expression levels in peripheral blood mononuclear cells and higher clinical disease activity. Finally, <italic>AA</italic> homozygosis for the intronic polymorphism rs2542109 was associated with the responder phenotype; however, <italic>USP18</italic> expression levels induced by IFNβ did not differ amongst MS patients carrying different rs2542109 genotypes.</p> </sec> <sec id="ene12193-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Altogether, these results point to a role of <italic>USP18</italic> in MS pathogenesis and the therapeutic response to IFNβ.</p> </sec> </abstract>