Effect of early psychosine accumulation in Krabbe Disease on CNS progenitor cells

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DESCRIPTION (provided by applicant): The molecular effect of early psychosine accumulation in Krabbe disease has not been studied in primary central nervous system (CNS) progenitor cell populations, specifically those of the oligodendroglial lineage responsible for proper myelination. By the time early onset Krabbe disease patients have presented with neurological symptoms, damage to the CNS may be irreparable due to early accumulation of abnormal levels of psychosine and its effect on vulnerable progenitor populations during critical developmental periods. Preliminary data suggests that physiologically relevant concentrations of psychosine are activating the previously described [13] redox/Fyn/c-Cbl pathway in primary oligodendrocyte/type-2 astrocyte progenitor cells (O-2A/OPCs). This pathway plays an important role in normal O-2A/OPC proliferation and migration. Further investigations on this pathway will better define cellular and molecular mechanisms of psychosine toxicity. Moreover, FDA-approved drugs in the NINDS II library will be screened to identify those that either ameliorate or exacerbate the toxic effects of psychosine. Rapid in vitro screening will be conducted using an automated adherent cell cytometry system. Candidate drugs will be further tested in vivo in the early onset Krabbe disease mouse model, the twitcher mouse. Developmental effects will be identified through immunohistochemical staining of brain and spinal cord sections and Western blot analysis. Behavioral and motor function tests, lifespan and symptom severity will be conducted as functional readouts of drug treatment. The goal is to protect early CNS development from effects of endogenous psychosine accumulation in early onset Krabbe patients through drug treatment intervention, ultimately to enable increased efficacy when used in combination with genetic and enzymatic replacement therapies. PUBLIC HEALTH RELEVANCE: Krabbe Disease is a debilitating genetic disorder of the nervous system that affects 1 in 100,000 live births in the United States (however the carrier rate for common mutations is estimated at 1 in 125 individuals) and results in severe neurological degeneration, demyelination, and death. At present there is no cure, and current therapeutic interventions have little beneficial effect in patients that have the more severe early onset (infantile) form of the disease. My research aims to identify abnormalities in early nervous system development due to alterations in normal progenitor cell biology and to screen FDA-approved drugs that ameliorate or exacerbate these effects to contribute to a multi-therapeutic approach that affords increased length and quality of life to patients that currently have no efficacious treatment options.