Affiliation:
1. Weill Institute for Neurosciences, Department of Neurology University of California San Francisco CA USA
2. Department of Anatomy and Cell Biology, Brody School of Medicine East Carolina University Greenville NC USA
Abstract
AbstractB cells play a key mechanistic role in the pathogenesis of multiple sclerosis (MS), a chronic neurological disease of the central nervous system with an autoimmune etiology. B cells contribute to disease initiation and progression by acting as professional antigen‐presenting cells as well as via secreting autoantibodies and proinflammatory cytokines. We have recently shown that the polyglutamine protein ataxin‐1, which was first linked to the movement disorder spinocerebellar ataxia type 1, also acts as a master regulator of B‐cell functions in the context of central nervous system autoimmunity. In fact, ataxin‐1–deficient mice display an aggravated manifestation of the MS disease model experimental autoimmune encephalomyelitis along with aberrant B‐cell functions. Consistent with this scenario, transcriptomic analysis of Atxn1‐null B cells highlighted distinct genetic signatures involved in cell activation, proliferation and antigen presentation. To further characterize the role of ataxin‐1, we profiled the noncoding transcriptome controlled by ataxin‐1 in the B‐cell compartment upon an encephalitogenic challenge. We show that two specific classes of noncoding RNAs, namely, processed pseudogenes and intergenic long noncoding RNAs, are differentially regulated along disease. Furthermore, pathway and protein network analyses on their putative protein‐coding gene targets found a significant enrichment in ontologies related to cell mitosis, together with molecular processes relevant to MS such as chitin metabolism. Altogether, these findings shed light on the possible contribution of noncoding RNAs to B‐cell biology and MS pathogenesis, and further establish the immunomodulatory role of ataxin‐1 in autoimmune demyelination.
Funder
National Multiple Sclerosis Society Texas Chapter
Subject
Cell Biology,Immunology,Immunology and Allergy