Tissue Culture Models of Lesch-Nyhan Disease

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DESCRIPTION (provided by applicant): Although the underlying gene defect in Lesch-Nyhan Disease (LND) is known and altered basal ganglia function strongly implicated in the manifestation of neurological and behavioral abnormalities, the mechanistic connection between the lack of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity and selective dopamine loss remains unclear. Cell models of HPRT-deficiency provide a powerful and efficient approach to understanding the important molecular perturbations and rapid evaluation of potential therapeutic agents. As observed in vivo, selection for HPRT mutations in rodent dopaminergic cell lines has resulted in a consistent decrease in cellular dopamine content. This has not been reversible by subsequent restoration of HPRT function. We propose to utilize existing cell models as well as recent advancements in stem cell technology that generate dopaminergic neurons in vitro to investigate alterations in dopaminergic specification and differentiation conferred by HPRT deficiency. Understanding the link between purine salvage and dopamine homeostasis is key to unraveling the pathological basis of LND, while identifying the temporal window wherein HPRT is required for normal dopaminergic tone provides a meaningful basis for the development of effective therapeutics, especially gene replacement strategies.