Dopaminergic neuronal (mal-)development in the absence of HGprt in Lesch-Nyhan Disease

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Lesch-Nyhan disease (LND) is a rare genetic disorder caused by a deficiency in the purine metabolism enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt). Although the neuropathological mechanism of HGprt deficiency is still unknown, it has become increasingly more evident that the mechanism may involve a dysfunction of the development of the dopaminergic system. The aim of this study was to examine some of the effects of the absence of HGprt on the development of the dopaminergic ventral midbrain and cerebral cortex in embryonic mice. We performed immunohistochemistry on cryosections of mice embryonic brains deficient for the HGprt enzyme and on explant assays from dissected embryonic midbrain areas of the same mouse model. We found that ventral midbrain dopaminergic neurons were affected in number and distribution, as well as the distribution of their subpopulations, in HGprt-deficient (HGprt-/0) embryonic mice. Furthermore, in cortical areas of these mice there was a decrease in cell proliferation but dopaminergic innervation seemed to be unaffected. Altogether, our results indicate that the HGprt deficiency in mouse might have various effects on the development of the dopaminergic system and of the cerebral cortex before birth. In addition, considering that HGprt is expressed in virtually all cells and at all ages, and since the neuropathological mechanisms might be explained by a combination of defects originating throughout embryonic and postnatal development, we emphasize the importance of studying the effects of HGprt deficiency on other neuronal systems and at other time points.
Faculteit der Sociale Wetenschappen