Glial Pathology in Globoid Cell Leukodystrophy

The goal of this dissertation was to examine the pathogenic potential of microglia in globoid cell leukodystrophy (GLD). We determined that psychosine, the pathogenic lipid toxin that accumulates in GLD, induced microglial transformation to globoid cells in vitro. Psychosine also induced matrix metalloproteinase (MMP)-3 in cultured glia. This mirrored the elevated expression of MMP-3 in the central nervous system (CNS) of twitcher mice, a murine model of GLD. Pharmacological inhibition or genetic ablation of MMP-3 blocked psychosine-induced globoid cell formation in vitro. These findings indicate that MMP-3 mediated psychosine-induced globoid cell formation. These findings were the first to relate the putative functions of MMPs in the CNS pathogenesis of a leukodystrophy. We next determined the effects of the extracellular matrix (ECM) in GLD pathology. We determined that tenascin-c (TnC), an ECM molecule, was aberrantly expressed in the brain of murine and human GLD. We determined that TnC enhances both psychosine-induced MMP-3 expression and globoid cel