Globoid Cell Leukodystrophy: Investigations into Pathogenesis and Therapy

Date of Award

Spring 5-15-2012

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Genetics & Genomics)

Degree Name

Doctor of Philosophy (PhD)

Degree Type



Globoid Cell Leukodystrophy: Investigations into Pathogenesis and Therapy


Jacqueline Ane Hawkins

Doctor of Philosophy in Biology and Biomedical Sciences (Molecular Genetics and Genomics)

Washington University in St. Louis

Dr. Mark S. Sands, Chairperson

Globoid Cell Leukodystrophy (GLD) is a lysosomal storage disorder resulting from the deficiency of the enzyme galactosylceramidase (GALC). In the absence of GALC, the toxic lipid psychosine (psy) accumulates in the nervous system. Psychosine causes death of oligodendrocytes, which leads to disregulation of myelin. The symptoms of GLD are nerologic and include irritability, sensory and motor deficits, peripheral neuropathy, cognitive decline and seizures. A mouse model of GLD is available and is biochemically authentic. The GALC-/- mouse, called the Twitcher (Twi) mouse has severe neurological symptoms including tremor, motor deficits, peripheral neuropathy and hind-limb wasting. These animals die by 40days of age. Although psy has long been accepted as the pathogenic molecule in GLD, very little is understood about how toxicity is facilitated. We have demonstrated that psy toxicity is a non-enantioselective process, which is likely membrane mediated. We also demonstrated that psy alters properties of both in vitro and in vivo membranes. These studies highlight the importance of membrane architecture in GLD.

Hematopoietic Stem Cell transplantation (HSCT) is the only clinically available treatment for GLD. Oxidative stress has been identified in a number of LSDs, including GLD. Cell culture experiments indicated that psy-induced oxidative stress could be ameliorated by the anti-oxidant N-acetyl-cysteine (NAC). We demonstrated that oxidative stress is also present in the nervous system of Twi mice. We then treated Twi mice with NAC, both alone and in combination with HCST. NAC treatment successfully lowered markers of oxidative damage and reduced markers of GLD at a early time point (20d). Markers of oxidative stress remained suppressed in NAC-treated animals, however the improvement in markers of disease was gone by terminal time points (37d). No improvements in lifespan, behavioral performance, or weight gain were observed in any of the treated groups. It is likely that oxidative stress is a consequence of disease, rather than a cause. Therefore treating it is of limited utility. It is possible that NAC could be therapeutic in the context of a more comprehensive combination therapy, targeted towards the primary causes of disease.


English (en)

Chair and Committee

Mark S Sands

Committee Members

Daniel Ory, Daniel Link, Jin-Moo Lee, Paul Schlesinger, Douglas Covey


Permanent URL: https://doi.org/10.7936/K7ST7MRM

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