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.
|Laukka, Jeremy J; Kamholz, John; Bessert, Denise et al. (2016) Novel pathologic findings in patients with Pelizaeus-Merzbacher disease. Neurosci Lett 627:222-32|
|Appikatla, Sunita; Bessert, Denise; Lee, Icksoo et al. (2014) Insertion of proteolipid protein into oligodendrocyte mitochondria regulates extracellular pH and adenosine triphosphate. Glia 62:356-73|
|Tatar, Carrie; Bessert, Denise; Tse, Harley et al. (2013) Determinants of central nervous system adult neurogenesis are sex, hormones, mouse strain, age, and brain region. Glia 61:192-209|
|Fitting, Sylvia; Ignatowska-Jankowska, Bogna M; Bull, Cecilia et al. (2013) Synaptic dysfunction in the hippocampus accompanies learning and memory deficits in human immunodeficiency virus type-1 Tat transgenic mice. Biol Psychiatry 73:443-53|
|Clark, Kristi; Sakowski, Lauren; Sperle, Karen et al. (2013) Gait abnormalities and progressive myelin degeneration in a new murine model of Pelizaeus-Merzbacher disease with tandem genomic duplication. J Neurosci 33:11788-99|
|Paintlia, Ajaib S; Paintlia, Manjeet K; Singh, Avtar K et al. (2010) Activation of PPAR-? and PTEN cascade participates in lovastatin-mediated accelerated differentiation of oligodendrocyte progenitor cells. Glia 58:1669-85|
|Tatar, Carrie L; Appikatla, Sunita; Bessert, Denise A et al. (2010) Increased Plp1 gene expression leads to massive microglial cell activation and inflammation throughout the brain. ASN Neuro 2:e00043|
|Swamydas, Muthulekha; Bessert, Denise; Skoff, Robert (2009) Sexual dimorphism of oligodendrocytes is mediated by differential regulation of signaling pathways. J Neurosci Res 87:3306-19|
|Paintlia, Ajaib S; Paintlia, Manjeet K; Singh, Inderjit et al. (2009) Combination therapy of lovastatin and rolipram provides neuroprotection and promotes neurorepair in inflammatory demyelination model of multiple sclerosis. Glia 57:182-93|
|Cerghet, Mirela; Skoff, Robert P; Swamydas, Muthulekha et al. (2009) Sexual dimorphism in the white matter of rodents. J Neurol Sci 286:76-80|
Showing the most recent 10 out of 15 publications