title: Defective structural RNA processing in relapsing-remitting multiple sclerosis.
abstract: BACKGROUND
  Surveillance of integrity of the basic elements of the cell including DNA, RNA, and proteins is a critical element of cellular physiology. Mechanisms of surveillance of DNA and protein integrity are well understood. Surveillance of structural RNAs making up the vast majority of RNA in a cell is less well understood. Here, we sought to explore integrity of processing of structural RNAs in relapsing remitting multiple sclerosis (RRMS) and other inflammatory diseases.
  
  
  RESULTS
  We employed mononuclear cells obtained from subjects with RRMS and cell lines. We used quantitative-PCR and whole genome RNA sequencing to define defects in structural RNA surveillance and siRNAs to deplete target proteins. We report profound defects in surveillance of structural RNAs in RRMS exemplified by elevated levels of poly(A) + Y1-RNA, poly(A) + 18S rRNA and 28S rRNAs, elevated levels of misprocessed 18S and 28S rRNAs and levels of the U-class of small nuclear RNAs. Multiple sclerosis is also associated with genome-wide defects in mRNA splicing. Ro60 and La proteins, which exist in ribonucleoprotein particles and play different roles in quality control of structural RNAs, are also deficient in RRMS. In cell lines, silencing of the genes encoding Ro60 and La proteins gives rise to these same defects in surveillance of structural RNAs.
  
  
  CONCLUSIONS
  Our results establish that profound defects in structural RNA surveillance exist in RRMS and establish a causal link between Ro60 and La proteins and integrity of structural RNAs.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. chase.spurlock@vanderbilt.edu.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Spurlock
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. john.t.tossberg@vanderbilt.edu.
authors.forename: John T
authors.initials: JT
authors.lastname: Tossberg
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. yan.guo@vanderbilt.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. subramaniam.sriram@vanderbilt.edu.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Sriram
authors.affiliation: Department of Mathematics, Vanderbilt University, Nashville, TN, 37232, USA. phil.crooke@vanderbilt.edu.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Crooke
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. tom.aune@vanderbilt.edu.|Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. tom.aune@vanderbilt.edu.|Medical Center North T3113, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN, USA. tom.aune@vanderbilt.edu.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Aune
mesh_terms: D001324:Autoantigens / Q000235:genetics*; D015870:Gene Expression; D056914:Genomic Structural Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007963:Leukocytes, Mononuclear; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000235:genetics* / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics*; D011061:Poly A / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics*; D020871:RNA Stability / Q000235:genetics; D012337:RNA, Ribosomal, 18S / Q000235:genetics; D012339:RNA, Ribosomal, 28S / Q000235:genetics; D020733:RNA, Small Cytoplasmic / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics*; D000099207:SS-A Antigen
chemical_list: D001324:Autoantigens; D010750:Phosphoproteins; D011061:Poly A; D012337:RNA, Ribosomal, 18S; D012339:RNA, Ribosomal, 28S; D020733:RNA, Small Cytoplasmic; D034741:RNA, Small Interfering; D012261:Ribonucleoproteins; C574674:La protein, human; C116006:RO60 protein, human; D000099207:SS-A Antigen