Characterization of the dopamine defect in primary cultures of dopaminergic neurons from hypoxanthine phosphoribosyltransferase knockout mice

Lesch-Nyhan disease (LND) is an X-linked metabolic disorder caused by lack of activity of the purine salvage enzyme hypoxanthine phosphoribosyltransfe rase (HPRT) and characterized by hyperuricemia and debilitating neurologica l manifestations. The mechanisms underlying the neuropathology are not well understood and the principal neurochemical lesion characterized to date is a deficiency of the dopamine system in the basal ganglia. To facilitate th e study of mechanism(s) by which HPRT deficiency causes the dopamine defect , we have compared the survival and dopamine phenotype of primary cultures of dopamine neurons derived from HPRT-deficient mice with the dopaminergic neurons from wild-type mice. The survival of dopaminergic neurons from both sources was promoted to an equal extent by glial cell line-derived neurotr ophic factor (GDNF), a potent survival factor for dopamine neurons in vitro . Although the survival of the HPRT-deficient neurons was indistinguishable from that of cells derived from wild-type counterparts, the HPRT-deficient cells demonstrated a persistent deficiency of dopamine content and dopamin e uptake with increasing neuritic differentiation, indicating that GDNF doe s not restore the normal phenotype in HPRT-deficient dopamine neurons despi te its well-known protective and regenerative properties in several neurode generation models. Nevertheless, the demonstration that GDNF trophic suppor t promotes the survival of these dopaminergic neurons will facilitate gaini ng a better understanding of the neuropathological mechanisms of LND by all owing a more extensive analysis of the cells central to the Lesch-Nyhan phe notype, the dopaminergic neurons of the basal ganglia.