Identifying Neurodegenerative Pathways underlying Cortical Demyelination in Progressive Multiple Sclerosis
Poyi (Bernie) Wu1, Ajai Tripathi2, Christina Volsko2, Ranjan Dutta1,2
1Cleveland Clinic Lerner College of Medicine, 2Department of Neuroscience, Lerner Research Institute, Cleveland Clinic
Background: Multiple Sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disease of the central nervous system (CNS). It affects more than 2.5 million individuals globally and is the number one cause of non-traumatic neurological disability in young adults in North America and Europe. 85% of MS patients have relapsing remitting MS (RRMS), marked by alternating episodes of relapses and remissions, while 15% of patients have Primary Progressive MS (PPMS), marked by continuous neurological decline since disease onset. Pathology of PPMS is unclear and current therapeutics are generally ineffective. Cortical demyelination is a hallmark of progressive MS and is correlated with neurological disability. Molecular pathways that underlie neuronal changes following demyelination remain unclear.
Objective: The current project aims to examine expression profile of genes and microRNAs (miRNAs), which are known to inhibit gene expression, within demyelinated regions in frontal cortex of progressive MS brains. The primary objective of the study is to identify mRNA and miRNA candidates that provide crucial information about molecular changes underlying neurodegeneration.
Methods: Using RNA sequencing data, the top 25 most significantly upregulated and 25 most significantly downregulated genes in demyelinated cortex of MS are identified. miRNAs that are significantly upregulated or downregulated are also identified. The genes and miRNA are cross-examined for inverse correlations using online bioinformatics tools miRNet, miRDB, TargetScan and Diana Tools. Target pathways that are associated with neurodegeneration are investigated. Immunohistochemistry and in-situ hybridization would be used to assess gene and miRNA expression in different cell types of MS tissue.
Results: 25 most significantly upregulated and 25 most downregulated genes in MS cortical lesions are selected. 66 significantly upregulated miRNAs are also identified. 10 inverse correlations between gene and miRNA are identified from this data pool. Of these 10 genes, APLNR (Apelin Receptor), CHRFAM7A (Cholinergic Receptor, Nicotinic, Alpha 7), RCAN2 (Regulator of Calcineurin 2), and SYT2 (Synaptotagmin) have demonstrated crucial roles, in literature, in either neuroprotection, neurodevelopment, or synaptic formation.
Conclusion: This study has identified 4 potential neurodegenerative pathways in MS cortical demyelination. APLNR, CHRFAM7A, RCAN2, SYT2, and their respective miRNA regulators may provide key information about the molecular processes underlying neurodegeneration in MS patients. The next phase of this study involves the characterization of these genes and miRNAs in MS cortical lesions using immunohistochemistry and in situ hybridization.
Grant Support: NIH, NINDS (NS096148) and the National Multiple Sclerosis Society, USA (RG 5298) to RD.