Oligodendrocyte RasG12V expressed in its endogenous locus disrupts myelin structure through increased MAPK, nitric oxide, and notch signaling

Abstract

Costello syndrome (CS) is a gain of function Rasopathy caused by heterozygous activating mutations in the HRAS gene. Patients show brain dysfunction that can include abnormal brain white matter. Transgenic activation of HRas in the entire mouse oligodendrocyte lineage resulted in myelin defects and behavioral abnormalities, suggesting roles for disrupted myelin in CS brain dysfunction. Here, we studied a mouse model in which the endogenous HRas gene is conditionally replaced by mutant HRasG12V in mature oligodendrocytes, to separate effects in mature myelinating cells from developmental events. Increased myelin thickness due to decompaction was detectable within one month of HRasG12V expression in the corpus callosum of adult mice. Increases in active ERK and Nitric Oxide (NO) were present in HRas mutants and inhibition of NO synthase (NOS) or MEK each partially rescued myelin decompaction. In addition, genetic or pharmacologic inhibition of Notch signaling improved myelin compaction. Complete rescue of myelin structure required dual drug treatments combining MAPK, NO, or Notch inhibition; with MEK + NOS blockade producing the most robust effect. We suggest that individual or concomitant blockade of these pathways in CS patients may improve aspects of brain function.

Main Points

The Costello mutation Ras-G12V in mature oligodendrocytes promotes increased activation of ERK (pERK, red). Additionally, Nitric Oxide is elevated in oligodendrocytes. Crosstalk and/or vertical activation of these signal pathways with Notch signaling (blue bracket) results in myelin decompaction (red inset). Pharmacological inhibition of the MEK, production of Nitric Oxide or Notch activation (Purple; with MEKi, L-NAME and GSI respectively), partially rescues myelin decompaction. Combined inhibition of MEK and Nitric Oxide fully rescues the phenotype. Interaction among the pathways is yet to be clarified.

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