Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Neurosciences


English (en)

Date of Award

January 2011

Degree Type


Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Mark Sands


Globoid-cell leukodystrophy: GLD, Krabbe's disease) is an autosomal recessive disease caused by a deficiency of the lysosomal enzyme galactosylceramidase: GALC). It results in altered catabolism of the myelin lipid Galactosylceramide. The disease predominantly affects the white matter of the CNS and the myelin sheath of the peripheral nerves. The infantile form of the disease is characterized by early onset between 3-6 months of age with symptoms of irritability, dysphagia, spasticity, cognitive and sensory deterioration and seizures. Death usually occurs by two years of age. Currently, hematopoietic stem cell transplantation is the only available option for patients with the disease. Inflammation is a prominent component of the disease and possibly plays an important role in determining the efficacy of therapy. The goal of the thesis is to understand the role of inflammation in the pathogenesis and treatment of GLD. In order to understand the role of inflammation, the murine model: twitcher) was used. The twitcher mouse is an authentic model of GLD. It is deficient in the same enzyme as that of the human counterpart and has similar phenotypic manifestations. Previous studies have shown that there is a synergistic therapeutic effect when bone marrow transplantation is combined with AAV2/5 mediated gene therapy. Our current study found that the synergistic effect could be further improved upon by targeting spinal cord with gene therapy in addition to the brain. The current study also found that AAV2/5 mediated gene therapy is associated with an increase in CD4 and CD8 T-cells and activated microglia in the brains and this could possibly limit the effectiveness of the viral vectors. Interestingly, addition of BMT to AAV2/5 reduced the T-cell and activated microglia, without further increasing the enzyme levels or decreasing the levels of toxic substance called psychosine in the CNS. This strongly suggests that BMT provides synergy by modulating inflammation. Other markers of inflammation that were highly elevated in the CNS, like the cytokine KC, were also reduced in mice that received treatment. Among all the cytokines that were measured, KC was the most highly elevated one in the CNS of the twitcher mice. KC is a strong chemoattractant to macrophages and neutrophils and it is also involved in oligodendrocyte precursor proliferation and migration. Since both components are important part of Krabbe's disease. The role of this cytokine was explored in further detail. Lack of KC or its receptor CXCR2 in the CNS or periphery or both did not alter the inflammation, oligodendrocyte proliferation or course of the disease in the twitcher mice. This could be explained by the compensatory increase in other cytokines and growth factors like MIP-2, FGF-2 and PDGF-BB. Although, KC and CXCR2 probably exert their effects in combination with other cytokines and growth factors, inflammation is clearly an important player in the pathogenesis and treatment of Krabbe's disease, but targeting the primary enzyme deficiency appears to be more important for therapy.


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