Messina Elisa, Micheli Vanna, Giacomello Alessandro
Department of Experimental Medicine and Pathology, University of Rome La Sapienza, viale Regina Elena 324, 00161 Rome, Italy.
Neurosci Lett. 2005 Feb 28;375(2):97-100. doi: 10.1016/j.neulet.2004.10.076. Epub 2004 Dec 10.
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.
莱施-奈恩病（LND）由次黄嘌呤鸟嘌呤磷酸核糖转移酶（HPRT）完全缺乏引起，其特征为神经功能缺损，病因不明。已有证据表明，它可能与基底神经节功能障碍有关，纹状体多巴胺纤维显著丧失。研究显示，莱施-奈恩病患者的细胞中会出现鸟嘌呤核苷酸耗竭。在本研究中，我们证明，用低水平（50 nM）霉酚酸（MPA）抑制肌苷单磷酸脱氢酶诱导的慢性鸟嘌呤核苷酸耗竭，会使人类神经母细胞瘤细胞系向神经元表型分化。MPA诱导的形态学变化在多巴胺能细胞系LAN5中比在胆碱能细胞系IMR32中更明显。与视黄酸诱导分化不同，MPA诱导的分化导致神经突生长和分支范围较小（类似于在培养的HPRT缺陷多巴胺能神经元中观察到的情况），并涉及p53、p21和bax上调以及bcl-2下调，且无p27蛋白积累。这些结果表明，HPRT缺乏后鸟嘌呤核苷酸耗竭可能导致大脑早期异常发育，主要影响基底神经节，而基底神经节具有最高的HPRT活性，这可能是LND特定神经行为特征的原因。
