Lesch-Nyhan disease (LND) is a developmental disorder caused by congenital deficiency of the purine salvage enzyme hypoxanthine-guanine phosphortbosyltransferase (HPRT). Affected patients have a characteristic neurobehavioral phenotype which includes dystonia, choreoathetosis, spasticity, cognitive disability, and aggressive and self-injurious behavior. Although multiple mutations responsible for the disorder have been cloned and the functions of the gene product extensively characterized, we still have a very limited understanding of the pathophysiological events which lead from the gene defect to the complex neurobehavioral phenotype. Prior studies of LND have revealed marked increases in de novo purine synthesis as well as depletion of basal ganglia dopamine. However, the relationship between these two abnormalities and the mechanisms by which HPRT deficiency causes depletion of basal ganglia dopamine remain unclear. A genetic HPRT-deficient (HPRT-) mouse model has been produced which has similar changes in brain purine and dopamine systems, making it an ideal tool to investigate potential relationships between purine and dopamine systems in the HPRT- deficient brain. In the present proposal, we plan to investigate these relationships. Our hypothesis is that a combination of purine deficiency and /or oxidant stress results in an early degenerative process of brain dopamine systems in the HPRT - mouse brain.
Specific Aim 1 involves a characterization of the neuronanatomical basis for reduced basal ganglia dopamine in the HPRT - mice at the light and electron microscopic levels. We will determine if HPRT - mice have reduced numbers of midbrain dopamine neurons or reduced dopamine fibers extending into the basal ganglia.
Aim 2 addresses the possibility that a deficiency of brain purines during development may be responsible for abnormal dopamine neuron develop or function. We will use nuclear magnetic resonance spectroscopy for 31-phosphorus (31P-NMRS) to measure brain purines during development, and determine if manipulation of brain purines during development can alter the degree of dopamine loss.
Aim 3 addresses the possiblity that increased de novo purine synthesis and turnover is associated with excessive generation of free radicals by xanthine oxidase, leading to oxidant stress and dysfunction of the dopamine neurons. We will measure indices of oxidant stress and determine if manipulating the degree of oxidant stress during development can alter the degree of dopamine loss. These studies have direct relevance for understanding mechanisms of pathogenesis and possible treatment strategies for LND. In addition, the studies have broader implications for understanding purine-dopamine relationships in normal and abnormal brain development.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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NST-2 Subcommittee (NST)
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Spinella, Giovanna M
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Johns Hopkins University
Schools of Medicine
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