Defective structural RNA processing in relapsing-remitting multiple sclerosis.
Charles F Spurlock, John T Tossberg, Yan Guo, Subramaniam Sriram, Philip S Crooke, Thomas M Aune
Author Information
- Charles F Spurlock: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. chase.spurlock@vanderbilt.edu.
- John T Tossberg: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. john.t.tossberg@vanderbilt.edu.
- Yan Guo: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. yan.guo@vanderbilt.edu.
- Subramaniam Sriram: Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. subramaniam.sriram@vanderbilt.edu.
- Philip S Crooke: Department of Mathematics, Vanderbilt University, Nashville, TN, 37232, USA. phil.crooke@vanderbilt.edu.
- Thomas M Aune: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. tom.aune@vanderbilt.edu.
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.
Autoantigens
Gene Expression
Genomic Structural Variation
High-Throughput Nucleotide Sequencing
Humans
Leukocytes, Mononuclear
Multiple Sclerosis, Relapsing-Remitting
Phosphoproteins
Poly A
RNA Splicing
RNA Stability
RNA, Ribosomal, 18S
RNA, Ribosomal, 28S
RNA, Small Cytoplasmic
RNA, Small Interfering
Ribonucleoproteins
Autoantigens
La protein, human
Phosphoproteins
RNA, Ribosomal, 18S
RNA, Ribosomal, 28S
RNA, Small Cytoplasmic
RNA, Small Interfering
RO60 protein, human
Ribonucleoproteins
Poly A
