The cause of Pelizaeus-Merzbacher Disease (PMD), a lethal neurological disorder, is mutations of the myelin proteolipid protein (PLP). The vast majority of PLP mutations in PMD disease are caused by over- expression of the native PLP gene. The phenotype of PMD is similar in many respects, at the level of the central nervous system, to multiple sclerosis (MS),. Both PMD and MS show oligodendrocyte (Olg) degeneration and axonal abnormalities including axonal degeneration. The cellular pathwaysthat induce apoptosis in glial cells and produce neuronal abnormalities caused by over-expression of native PLP have not been investigated. Analyses of the mechanisms causing apoptosis and axonal abnormalities in animals that over-express PLP may also be relevant to understanding the mechanisms causing these same CNS abnormalities in MS. In our previous studies, we showed that over-expression of PLP functions as an autocrine toxic molecule in Olgs and as a paracrine toxic molecule to neurons. We also showed that the pH of extracellular space in PLP over-expressing mice is highly acidic and contributes to neuronal death. Our proposal addresses two issues regarding over-expression of PLP: first, identify the pathwaysthat induce apoptosis and, second, determine how mitochondria regulate life-death decisions in mice that over- express native PLP. Our preliminary evidence suggests that the intrinsic mitl apoptotic pathway is activated when PLP is over-expressed, that ATP levels are grossly reduced, and the normal mitl membrane potential depolarized. We hypothesize that the primary cause underlying these sub-cellular abnormalities is the association of PLP with mitochondria.
Our specific aims are: (1) show that over-expressionof the PLP1 gene activates the intrinsic mitl apoptotic pathway in vivo and in vitro;(2) show that respiration is severely compromised, as manifested by a decrease in ATP levels, alterations in the mitl membrane potential (Dy), and reactive oxygen species;(3) test the hypothesis that depolarization of the mitochondrial membrane potential leads to cellular acidification; and (4) demonstrate that the cause of the above described abnormalities is due to the physicalassociation of PLP with mitl membranes.
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