Human neural stem cells: a model system for the study of Lesch-Nyhan disease neurological aspects
Human neural stem cells: a model system for the study of Lesch-Nyhan disease neurological aspects
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DOI：
10.1093/hmg/ddq072
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发表时间：
2010-05-15
影响因子：
3.5
通讯作者：
Invernici, Gloria
中科院分区：
文献类型：
--
作者：
Cristini, Silvia;Navone, Stefania;Invernici, Gloria
对莱氏病（LND）人脑的研究对于理解突变型次黄嘌呤磷酸核糖转移酶（HPRT）如何导致神经元功能障碍至关重要。由于LND是一种由HPRT酶缺乏引起的罕见遗传性疾病，携带这种突变的人类神经干细胞（hNSCs）是描述HPRT缺乏症后果和开发新治疗方法的宝贵来源。在我们的研究中，我们研究了HPRT缺乏对从人LND胎脑分离的hNSCs中神经元分化的影响。我们检测了一些神经元分化所必需的转录因子和参与多巴胺（DA）生物合成途径的标记基因的表达。LND hNSCs显示出几种转录因子和DA标志物的异常表达。HPRT缺陷的多巴胺能神经元也表现出神经突生长的显著缺陷。这些结果代表了LND hNSCs异常神经发生的直接实验证据，并表明其他管家基因在神经发育疾病中的发育作用。此外，LND hNSCs暴露于视黄酸培养基引起多巴胺能神经元的产生。对LND的神经功能障碍缺乏准确的了解，阻碍了有用治疗方法的发展。这些结果证明了LND hNSCs中的异常神经发生，并表明HPRT基因在神经发育中的作用。这些细胞联合收割机结合了神经发育模型和人类神经起源的特点，为研究HPRT缺陷的病理生理学提供了重要工具，并更广泛地证明了人类神经干细胞在研究疾病和识别潜在疗法方面的实用性。
The study of Lesch-Nyhan-diseased (LND) human brain is crucial for understanding how mutant hypoxanthine-phosphoribosyltransferase (HPRT) might lead to neuronal dysfunction. Since LND is a rare, inherited disorder caused by a deficiency of the enzyme HPRT, human neural stem cells (hNSCs) that carry this mutation are a precious source for delineating the consequences of HPRT deficiency and for developing new treatments. In our study we have examined the effect of HPRT deficiency on the differentiation of neurons in hNSCs isolated from human LND fetal brain. We have examined the expression of a number of transcription factors essential for neuronal differentiation and marker genes involved in dopamine (DA) biosynthetic pathway. LND hNSCs demonstrate aberrant expression of several transcription factors and DA markers. HPRT-deficient dopaminergic neurons also demonstrate a striking deficit in neurite outgrowth. These results represent direct experimental evidence for aberrant neurogenesis in LND hNSCs and suggest developmental roles for other housekeeping genes in neurodevelopmental disease. Moreover, exposure of the LND hNSCs to retinoic acid medium elicited the generation of dopaminergic neurons. The lack of precise understanding of the neurological dysfunction in LND has precluded development of useful therapies. These results evidence aberrant neurogenesis in LND hNSCs and suggest a role for HPRT gene in neurodevelopment. These cells combine the peculiarity of a neurodevelopmental model and a human, neural origin to provide an important tool to investigate the pathophysiology of HPRT deficiency and more broadly demonstrate the utility of human neural stem cells for studying the disease and identifying potential therapeutics.