Micro-RNA in MSFriday, October 04, 2013, 17:30 - 17:42
Identification of microRNAs that control remyelination efficiency in multiple sclerosis brains R. Dutta, A. Chomyk, S. Deckard, A. Chang, M. Ribuado, R. Fox, B. Trapp (Cleveland, US)
Multiple sclerosis (MS) is an inflammatory-mediated demyelinating disease of the human central nervous system. Generation of new myelin forming cells and repair of myelin requires generation of new oligodendrocytes from well-characterized progenitor cells. These cells, albeit present at reduced levels in chronically demyelinated lesions, produce new oligodendrocytes that fail to mature and remyelinate MS lesions. In a recent study, we reported increased remyelination in cortical lesions compared to white matter lesions.
To better understand mechanisms that influence this differential maturation of progenitors and remyelination, we performed comparative analysis of microRNA (miRNAs) between white and grey matter lesions to identify the regulatory factors affecting this process.
Our comparative analysis shows, 72 miRNAs changed in white matter lesions compared to 70 in grey matter lesions. Interestingly, 30 of these miRNAs were common between the two tissue types. Among the common miRNAs, miR-219, mir-338 and let7b were decreased in both lesion types and were localized to oligodendrocytes in MS brains using insitu hybridization. Bioinformatic analysis also revealed reciprocal direction of fold changes in the common miRNAs and their targets. Major biological pathways that are targets of these miRNAs include, notch and Wnt signaling, the key pathways associated with remyelination. The miRNA, miR-27b was decreased in white matter lesions, expressed by astrocytes in MS brains and was increased in grey matter lesions. mRNA and protein levels of CD44, a major target of this miRNA was inversely correlated with the miRNA level in these tissues.
We therefore identify a cohort of miRNAs may be involved in failure of oligodendrocyte progenitor differentiation and maturation and explain the differential remyelination efficiency observed in MS brains.
Elucidation of the mechanisms that contribute to failed remyelination should lead to novel therapeutics that delays the progression of permanent neurological disability in individuals with multiple sclerosis.
Grant Support: National MS Society (RG-4280A) and NIH (NINDS-NS35058)
Ranjan Dutta has served as a consultant for Biogen Idec and received grant support from Pfizer Inc, USA. Ansi Chang, Anthony Chomyk, Sadie A Deckhard, Michael Ribaudo has nothing to disclose. Robert Fox has received personal consulting fees from Allozyne, Avanir, Biogen Idec, Novartis, Questcor, Teva, and Xenoport. Bruce D Trapp has served as a consultant for TEVA, Serono, Biogen Idec, Novartis and have received grant support from Biogen Idec and Pfizer Inc, USA.