title: Striatal neurodevelopment is dysregulated in purine metabolism deficiency and impacts DARPP-32, BDNF/TrkB expression and signaling: new insights on the molecular and cellular basis of Lesch-Nyhan Syndrome.
abstract: Lesch-Nyhan Syndrome (LNS) is a neurodevelopmental disorder caused by mutations in the gene encoding the purine metabolic enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). This syndrome is characterized by an array of severe neurological impairments that in part originate from striatal dysfunctions. However, the molecular and cellular mechanisms underlying these dysfunctions remain largely unidentified. In this report, we demonstrate that HPRT-deficiency causes dysregulated expression of key genes essential for striatal patterning, most notably the striatally-enriched transcription factor B-cell leukemia 11b (Bcl11b). The data also reveal that the down-regulated expression of Bcl11b in HPRT-deficient immortalized mouse striatal (STHdh) neural stem cells is accompanied by aberrant expression of some of its transcriptional partners and other striatally-enriched genes, including the gene encoding dopamine- and cAMP-regulated phosphoprotein 32, (DARPP-32). Furthermore, we demonstrate that components of the BDNF/TrkB signaling, a known activator of DARPP-32 striatal expression and effector of Bcl11b transcriptional activation are markedly increased in HPRT-deficient cells and in the striatum of HPRT knockout mouse. Consequently, the HPRT-deficient cells display superior protection against reactive oxygen species (ROS)-mediated cell death upon exposure to hydrogen peroxide. These findings suggest that the purine metabolic defect caused by HPRT-deficiency, while it may provide neuroprotection to striatal neurons, affects key genes and signaling pathways that may underlie the neuropathogenesis of LNS.
authors.affiliation: Department of Pediatrics, Division of Genetics/Rady Children's Hospital, University of California San Diego School of Medicine, La Jolla, California, United States of America.
authors.forename: Ghiabe-Henri
authors.initials: GH
authors.lastname: Guibinga
authors.affiliation: Department of Pediatrics, Division of Genetics/Rady Children's Hospital, University of California San Diego School of Medicine, La Jolla, California, United States of America.
authors.forename: Nikki
authors.initials: N
authors.lastname: Barron
authors.affiliation: Department of Pediatrics, Division of Genetics/Rady Children's Hospital, University of California San Diego School of Medicine, La Jolla, California, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Pandori
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics* / Q000378:metabolism; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D007926:Lesch-Nyhan Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020813:Receptor, trkB / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D017382:Reactive Oxygen Species; D007041:Hypoxanthine Phosphoribosyltransferase; D020813:Receptor, trkB