Krabbe Disease (KD) is a rare neurologic disease characterized by progressive demyelination in the central and peripheral nervous systems (CNS and PNS, respectively). KD typically affects infants in the first few months of life and quickly progresses to overall clinical decline and death within months. The only available treatment for KD is Hematopoietic Stem Cell Transplantation (HSCT), which has limited therapeutic applications as it must be administered before the onset of symptoms occur, and unfortunately has partial long term efficacy despite early intervention. KD is due to inheritable mutations in the GALC gene leading to a loss- of-function in the lysosomal enzyme galactosylceramidase (GalC), responsible for the degradation of galactosylceramide and a structurally related metabolite known as psychosine. Psychosine accumulates in patients with KD and is thought to be responsible for the death of myelin forming cells in the CNS (oligodendrocytes) and PNS (Schwann cells). Recent data suggest that psychosine toxicity in KD may also target neurons primarily, causing axonal and neuronal degeneration even before and independent of demyelination. It is also hypothesized that limitations of HSCT in KD patients may be due to a limited restorative effect of myelination in the PNS, which may cause severe weakness and autonomic dysfunction leading to sudden death. However, the extent of the contribution of PNS pathology to symptoms in KD has not been determined. Similarly, the primary role of KD on neurons, independent of demyelination, has not been determined. To investigate the role of cell autonomy in KD, this project will use a conditional deletion strategy in mice to specifically ablate GalC function in Schwann cells or neurons, independently. These mice will then be evaluated and characterized for disease progression by clinical, electrophysiological, pathological and molecular measures. Additionally, we will study neurons derived from fibroblasts from KD patients, in vitro, to determine if KD neurons are inherently susceptible to pathology. Our data will provide information on the interplay between glia and neurons in neurodegeneration, a central emerging question in most neurological diseases, including the leukodystrophies. In addition, findings from this proposal will help to understand the disease mechanisms of KD and the limitations of HSCT, which will allow us to develop better therapies for KD and similar demyelinating diseases in the future.
Krabbe Disease (KD) is a rare neurologic disorder that typically affects infants within the first few months of life and relentlessly progresses to cognitive decline and death within a matter of months. The goal of this research is to advance our understanding of the basic mechanisms of KD so that better treatment can become available.
