Disease Mechanisms of Pontocerebellar Hypoplasia Type 10

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PROJECT SUMMARY/ABSTRACT Degeneration of brain or spinal cord neurons is associated with many untreatable neurological disorders and leads to a gradual decline in cognitive and motor function, and eventual death. While more prevalent in aged individuals, neurodegenerative disease onset is variable and can begin in childhood. There are no effective therapies for the majority of patients, likely due to our limited understanding of disease etiology. Inherited neurodegenerative disorders are commonly caused by genetic mutations in RNA binding proteins that regulate RNA biogenesis. In order to develop therapeutics for this class of disorders, it will be critical to understand how RNA binding proteins function in normal and diseased states, and whether molecular changes are amenable to correction. Our preliminary data suggests mRNA processing may be significantly affected in cases of inherited childhood motor neuron degeneration. To test our hypothesis that mRNA processing defects cause pediatric motor neuron disease, we have created human stem cell- and animal-based models to correlate molecular changes with disease pathology. We will apply high-throughput sequencing, electrophysiology, histology and behavioral approaches to our novel disease models to pinpoint pathogenic transcriptional mRNA isoforms expressed as a consequence of the RNA binding protein mutation as well as test a candidate targeted gene- based therapy.