Advisory Committee Chair
Advisory Committee Members
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Since the initial report identifying mutations in GFAP as the primary genetic defect in the astrogliopathy Alexander Disease (AxD) much progress has been made in elucidating the molecular details underpinning the pathogenic role of mutant GFAP in astrocytes. In particular, data collected from mouse, fly, and cell culture models of AxD have isolated several prominent cellular changes that are associated with mutant GFAP expression including oxidative stress, proteasome inhibition, reduced expression of the astrocyte glutamate transporter GLT-1, and loss of neurons; these models have also successfully recapitulated the pathological hallmark of AxD--protein aggregates known as Rosenthal fibers (RFs). To date, however, much less attention has been focused on collecting data from AxD patient brain. As such, the current work sought to confirm and extend the previous findings from AxD model systems to patient neocortex by performing a proteomic study on patient and control neocortical tissue using gel-enhanced liquid chromatography-tandem mass spectrometry (GeLC-MS/MS). The datasets generated by this approach confirmed many of the previously reported findings from AxD model systems; in addition, numerous novel features of AxD neocortex were described such as decreased abundance of the enzyme, glutamine synthetase, and signs of oligodendrocyte cell loss. Other findings of interest included the identification of atrogin-1 as a novel RF-associated protein and as a candidate AxD biomarker; the latter of which relates to the fact that this report is the first to document atrogin-1 at the protein level in the brain of any species. Finally, this study uncovered evidence using bioinformatics that cellular pathways related to integrins and the actin cytoskeleton are activated in AxD and suggested a role for RhoA/ROCK signaling in mediating this response. As small molecule inhibitors of ROCK (e.g. Fasudil) are currently approved for use in humans, these findings may suggest a therapeutic role for these compounds in the clinical management of AxD.
Flint, Daniel L., "Proteomic Clues to the Pathogenesis of Alexander Disease" (2012). All ETDs from UAB. 1654.