MicroRNA (miRNA) are short, non-coding RNAs that can significantly affect gene expression. In Multiple Sclerosis (MS), an autoimmune disease targeting the central nervous system, much is understood about how the immune system promotes neurodegeneration in early stages of disease. However, studies on secondary progressive MS (SPMS) demonstrate that the continued role of the immune system in disease progression is not well characterised. As key regulators of gene expression, identifying changes of miRNA expression patterns in SPMS tissues will provide insight into disease mechanisms at this stage. Using next-generation sequencing, a comprehensive miRNA expression profile of CD4+ T-cells was attained, and the NanoString nCounter miRNA array was used to the same effect in normal appearing white matter (NAWM) of SPMS individuals. RT-qPCR confirmed results from these methods, and further explored associated gene expression changes, such as common targets of dysregulated miRNAs, and genes essential to miRNA biogenesis and DNA methylation. The role of DNA methylation on miRNA dysregulation was also explored using Illumina 450k arrays. A convergence of several factors, led by changes in miRNA expression, was found to reduce activity of CD4+ T-cells in SPMS. Broad down-regulation of miRNAs was identified, a novel observation in MS miRNA studies, caused by a reduction of miRNA biogenesis molecules. This resulted in: up-regulation of SOCS6, negative lyregulating T-cell activation; and de novo hypermethylation driven by miR-29b associated up-regulation of DNMT3b. These findings point towards CD4+ T-cell shaving a diminished role in SPMS. Additionally, analysis of miRNA expression inNAWM also identified miR-29b down-regulation, amongst other miRNAs, that may act to prevent oligodendrocyte maturation and thus hinder remyelination. This suggests that neurodegenerative mechanisms are fully operational in NAWM during SPMS. In conclusion, the mechanisms of disease progression in SPMS are now better understood. miRNA down-regulation prompts CD4+ T-cells to take a backseat, and neurodegeneration assisted by miRNA dysregulation, is primed to occur in NAWM.
|Date of Award||7 Oct 2017|
|Supervisor||Lotti Tajouri (Supervisor), Jeannette Lechner-Scott (Supervisor) & Rodney J. Scott (Supervisor)|