Ataxin-1 controls the expression of specific non-coding RNAs in B cells upon autoimmune demyelination.

B 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 pro-inflammatory cytokines. We have recently shown that the polyglutamine protein ataxin-1, which was first linked to the movement disorder spinocerebellar ataxia type 1 (SCA1), also acts as a master regulator of B cell functions in the context of CNS autoimmunity. In fact, ataxin-1 deficient mice display an aggravated manifestation of the MS disease model experimental autoimmune encephalomyelitis (EAE) 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 non-coding transcriptome controlled by ataxin-1 in the B cell compartment upon an encephalitogenic challenge. We show that two specific classes of non-coding RNAs, namely processed pseudogenes and intergenic long non-coding 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 non-coding RNAs to B cell biology and MS pathogenesis, and further establish the immunomodulatory role of ataxin-1 in autoimmune demyelination.