: The long-term goal of these studies is to establish the mechanism by which mutations affect oligodendrocyte differentiation and overall brain development. The focus is on the myelin proteolipid protein (PLP) gene, which constitutes 50 percent of myelin protein. Even conservative amino acid mutations in this protein are devastating to norrnal brain development. We will test the hypothesis that these PLP mutations induce oligodendrocyte cell death by affecting intracellular translocation of the protein. In particular, we have evidence that defective PLP increases its association with the chaperone, calreticulin, which is also involved in calcium homeostasis. Up- or down regulation of calreticulin induces calcium dysregulation and increased sensitivity to apoptosis. Calcium homeostasis is dysregulated in jimpy oligodendrocytes, and we will study whether the increase in calreticulin is involved in that dysregulation and in the increased apoptosis found in mutant oligodendrocytes. In addition, we have identified a new DM20-related protein expressed in the peripheral nervous system. We will investigate what this protein is and whether it has unique functions with respect to glial cell survival and/or differentiation. These studies develop from basic investigations on the translation and translocation of the PLP protein to studying how the oligodendrocyte expressing defective PLP/DM20 protein changes its developmental pattern and eventually dies. We have generated transgenic mice that overexpress enhanced green fluorescent protein (EGFP), which can be visualized in live tissue. In the mutants, oligodendrocytes begin to myelinate axons, but there is a high level of oligodendrocyte cell death, and eventual hypomyelination. We will use these mice to visualize this process, i.e., the differentiation and interaction of mutant oligodendrocytes with axons. We will be able to assess when and where these cells start to die. We have been investigating one element in the interaction of oligodendrocytes and axons that normally enhances their survival: neuregulins. We will study whether the mutant cells can respond to neuregulins and whether the downstream survival signaling system for neuregulins, activated Akt, can enhance survival of mutant oligodendrocytes.
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