Date of Completion

11-12-2013

Embargo Period

11-12-2013

Keywords

Globoid cells, microglia, psychosine, matrix metalloproteinase, M1/M2 phenotype, oligodendrocytes

Major Advisor

Stephen Crocker, Ph.D.

Associate Advisor

Richard Mains, Ph.D.

Associate Advisor

Nada Zecevic, M.D., Ph.D.

Associate Advisor

Lauren Sansing, M.D.

Associate Advisor

Elisa Barbarese, Ph.D.

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

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 cell formation in microglia. Additionally, TnC altered the phenotype of microglia and globoid cells from a protective toward a harmful phenotype toward oligodendrocytes in co-cultures. These findings suggest that TnC modulates cellular behaviors that may contribute to the GLD pathogenesis.

Overall, results of this thesis determined that microglial responses to psychosine are a primary event of the pathogenesis in GLD. Overall, the findings of this dissertation have provided a new level to our understanding of GLD pathogenesis and provided new potential therapeutic targets to treat GLD.

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