MS is a neuroinflammatory disease characterized by a progressive loss
of myelin and a failure of oligodendrocyte (OL)-mediated remyelination,
particularly in the progressive phases of the disease. An improved
understanding of the signaling mechanisms that control differentiation
of OL precursors may lead to the identification of new therapeutic
targets for remyelination in MS. About 100 mammalian Protein Tyrosine Phosphatases (PTPs) are known, many of which are involved in signaling
both in health and disease. We have undertaken a systematic genomic
approach to evaluate PTP gene activity in multiple sclerosis
autopsies and in related in vivo and in vitro models of the disease.
This effort led to the identification of Dusp15, a PTP previously
believed to be expressed only in testis, as being transcriptionally
regulated during OL differentiation and in MS lesions. Subsequent RNA
interference studies revealed that Dusp15/VHY is a key regulator of OL
differentiation. Finally, we identified PDGFR-beta and SNX6 as novel and
specific Dusp15 substrates, providing an indication as to how this PTP
might exert control over OL differentiation.
Several lines of evidence support the observation that remyelination in
MS is partially impaired because of the inability of OPCs to
differentiate into myelinating OL. During the last decade, several inhibitory pathways of OL differentiation were identified, like Wnt, Notch-1, LINGO/RhoA. In this study the modulation of Protein Tyrosine Phosphatases. was examined
These are a group of enzymes that remove phosphate groups from phosphorylated tyrosine
residues on proteins. Protein tyrosine (pTyr) phosphorylation is a
common post-translational (that occurs after the protein is made from RNA) modification that can create novel recognition
motifs for protein interactions and cellular localisation, affect
protein stability, and regulate enzyme activity. In this study they used a number of different approaches to find things that change during myelination. They looked at MS tissue, mouse EAE tissue and tissue from myelination assays and came up with around ten PTP that looked interesting and did further work and one PTP called Dual specificity protein phosphatase 15 was identified that was thought to be regulated during the maturation of oligodendrocytes. Silencing Dusp15 inhibited oligodendrocyte diffferentiation.This factor may act on platelet derived growth factor receptor, which is known to be involved in the proliferation of oliogodendrocyte precursor cells. The other molecule it acts on is sorting nexin 6 as well as other molecules. Therefore augmenting Dusp15 may be a method to promote remyelination.
CoI: None
This study was performed by Merck-Serono, a large MS drug company; they are obviously hunting for targets for remyelination. I wonder if this was the most promising target found in their searches?
Labels: oligodendrocyte