Dr Una Fitzgerald and her team in National University of Ireland (NUI) Galway explore the remyelination and demyelination process in the brain.
Project Title
Polymer-mediated delivery of endoplasmic reticulum stress-altering siRNA to oligodendroyctes in a cerebellar rat brain slice model of de- and remyelination.
Research Summary
Loss of myelin can be repaired by the generation of new myelin by oligodendrocyte precursor cells (OPCs). These cells produce myelin during the natural development of the nervous system and can also repair areas in the adult brain that have been demyelinated during MS. Although OPCs are still present in the adult brain, this repair function is impaired over time, which leaves axons prone to neurodegeneration. Making myelin requires OPCs to make vast amounts of lipids and proteins and this may place it under a specific type of stress called endoplasmic reticulum stress (ER stress). This stress can be “good” in that it can prompt the cell to adapt and increase its capacity for making proteins and lipids. If it is severe however it may be “bad” and cause cell death. We hypothesise that signaling pathways initiated by ER stress may play a role in myelination and may represent a new avenue through which to influence the ability of OPCs to make myelin. We are examining this pathway also because in the past, we discovered that ER stress signalling proteins are present at raised levels in active MS lesions found in post-mortem human tissue samples.
We have already studied the normal development of myelination in white matter tracts through histological staining and we observed ER stress sensors (ATF6, IRE1) “switching on” just before myelin proteins appeared and during active myelination. The number of cells that showed activation of these sensors was significantly higher than the number found before myelination began or after it had been completed. Proteins that are known to be upregulated by ER stress (GRP78, GRP94 and PDI) were also at significantly higher levels than before myelination had been initiated. Dual staining of these proteins showed they were present in oligodendrocyte cells but other processes will also be occurring in the developing tissue. In order to find out what effect ER stress may be having specifically on myelination in particular, we are assessingplan to assess the effects of blocking ER stress signaling in a purified population of OPCs in tissue culture. If it is possible to influence myelination in purified OPCs through ER stress signalling, we can then apply those the same approach methods in order to establish whether or not it ER stress may also influences re-myelination. Using organotypic brain slice cultures we are able to study remyelination of nerves by OPCs, as a model of in a way that is more relevant to what occurs in the body. After chemical demyelination we can apply drugs to assess the potential role of ER stress as a new therapeutic avenue for remyelination.