title: Guanine nucleotide depletion induces differentiation and aberrant neurite outgrowth in human dopaminergic neuroblastoma lines: a model for basal ganglia dysfunction in Lesch-Nyhan disease.
abstract: Lesch-Nyhan disease (LND), caused by complete deficiency of hypoxanthine guanine phosphoribosyltransferase (HPRT), is characterized by a neurological deficit, the etiology of which is unknown. Evidence has accumulated indicating that it might be related to dysfunction of the basal ganglia with a prominent loss of striatal dopamine fibers. Guanine nucleotide depletion has been shown to occur in cells from Lesch-Nyhan patients. In this study we demonstrate that chronic guanine nucleotide depletion induced by inhibition of inosine monophosphate dehydrogenase with low levels (50 nM) of mycophenolic acid (MPA) lead human neuroblastoma cell lines to differentiate toward the neuronal phenotype. The MPA-induced morphological changes were more evident in the dopaminergic line LAN5, than in the cholinergic line IMR32. MPA-induced differentiation, unlike that induced by retinoic acid, caused a less extensive neurite outgrowth and branching (similar to that observed in cultured HPRT-deficient dopaminergic neurons) and involved up-regulation of p53, p21 and bax, and bcl-2 down-regulation without p27 protein accumulation. These results suggest that guanine nucleotide depletion following HPRT deficiency, might lead to earlier and abnormal brain development mainly affecting the basal ganglia, displaying the highest HPRT activity, and could be responsible for the specific neurobehavioral features of LND.
authors.affiliation: Department of Experimental Medicine and Pathology, University of Rome La Sapienza, viale Regina Elena 324, 00161 Rome, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Messina
authors.forename: Vanna
authors.initials: V
authors.lastname: Micheli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Giacomello
mesh_terms: D001479:Basal Ganglia / Q000002:abnormalities* / Q000378:metabolism* / Q000503:physiopathology; D001480:Basal Ganglia Diseases / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D049108:Cell Enlargement / Q000187:drug effects; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006150:Guanine Nucleotides / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000172:deficiency; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007926:Lesch-Nyhan Syndrome / Q000378:metabolism* / Q000503:physiopathology; D008959:Models, Neurological; D009173:Mycophenolic Acid / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009447:Neuroblastoma; D016900:Neurofilament Proteins / Q000187:drug effects / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D006150:Guanine Nucleotides; D016900:Neurofilament Proteins; C051774:neurofilament protein H; D014212:Tretinoin; D007168:IMP Dehydrogenase; C488211:IMPDH1 protein, human; D007041:Hypoxanthine Phosphoribosyltransferase; D009173:Mycophenolic Acid