Identifying novel targets and mechanistic role of 8,9 unsaturated sterol accumulation on enhancement of oligodendrocyte formation

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Project Summary Multiple Sclerosis (MS) is a debilitating disease that is characterized by loss of oligodendrocytes in the brain. A potential therapeutic angle for MS is through the increased differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes. Increasing differentiation of OPCs is a viable therapeutic option because they are a stem cell population that is found in the adult brain with the ability to differentiate, albeit typically at lower rates than needed to alleviate the symptoms of MS. Different labs have conducted high throughput screens to identify novel small molecules that lead to increased OPC differentiation. In work from our lab, we identified a unifying mechanism of the hits from these screens. Each small molecule inhibited one of three steps within the cholesterol biosynthesis pathway, which we then identified the accumulation of the 8,9 unsaturated sterols from these steps as being the mechanism of action. Our lab has evaluated the accumulation of different sterols and the cholesterol biosynthesis pathway for other novel targets. In this proposal, we plan to elucidate different targets within the cholesterol biosynthesis pathway and evaluate potential mechanisms by which these sterols enhance oligodendrocyte formation. In Aim 1, we have developed tools and small molecules to target previously overlooked enzymes within the cholesterol biosynthesis pathway, SC4MOL, NSDHL, and HSD17B7. Potential inhibition of these three enzymes would similarly lead to accumulation of 8,9-unsaturated sterols. Therefore, we hypothesize that these enzymes provide additional therapeutic targets. In Aim 2, we propose that two parallel pathways within the cholesterol biosynthesis pathway have unique effects on oligodendrocyte differentiation. In Aim 3, we have identified two potential signaling mechanisms in which 8,9-unsaturated sterols promote OPC differentiation. Transcriptomic and proteomic analyses have been done to determine different downstream signaling pathways by which these 8,9-unsaturated sterols act through to promote OPC differentiation. Two different signaling pathways have been implicated, and this proposal evaluates whether they are the mechanism. Taken together, the experiments outlined in this proposal will provide key new findings in the search and development of remyelinating therapeutics. Both new targets (Aim 1 and 2) and the mechanism of these sterols (Aim 3) will provide a more complete picture and potential therapeutic strategies to target OPCs to repopulate oligodendrocytes in the brain.