Chapter 4 . 2 Pathway analysis of microRNA expression in multiple sclerosis lesions

MicroRNA expression profiles of patients with multiple sclerosis (MS) have revealed differences from healthy controls both in cells from the peripheral circulation and in specimens from white matter lesions. Here, we studied differences in microRNA expression and in their predicted mRNA targets in white and grey matter lesions of patients with MS as compared with white and grey matter brain tissue from controls. Post-mortem brain tissue was obtained from patients with MS and controls. By means of immunohistochemistry, five chronic active white matter lesions from patients with mainly white matter lesions, five subpial grey matter lesions from patients with mainly grey matter lesions, and five white and five grey matter brain samples from controls were selected. Differences in microRNA and mRNA expression were determined using microarrays. As compared with control tissue, 41 microRNAs were differentially expressed in white matter MS lesions, 17 microRNAs in grey matter MS lesions, and 6 microRNAs in both. In addition, 2222 mRNAs were differentially expressed in white matter lesions, 959 mRNAs in grey matter lesions, and 183 mRNAs in both tissues. Differentially expressed microRNAs were selected for assessment of their predicted differentially expressed mRNA targets using the algorithm from TargetScan Human. These differentially expressed putative mRNA targets from these microRNAs are involved in myelin formation, neurite growth, synapse function, cell growth and death, mitochondrial functioning, ion channels, the mTOR pathway, and inflammation. In addition, to investigate the expression of microRNAs in more detail, in situ hybridisation was performed on brain tissue. MicroRNA-219, expressed by oligodendrocytes, was clearly decreased in white and grey matter multiple sclerosis lesions. Here, we show abundant alterations in microRNA and their predicted mRNA targets in white and grey matter lesions of patients with MS. This is indicative of widespread perturbations of microRNAs in MS, and is suggestive of their potential contribution to the pathogenesis of MS.