Human neural stem cells: A model system for the study of Lesch-Nyhan disease neurological aspects

Silvia Cristini, Stefania Navone, Laura Canzi, Francesco Acerbi, Emilio Ciusani, Uros Hladnik, Paola de Gemmis, Giulio Alessandri, Augusto Colombo, Eugenio Parati, Gloria Invernici

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article numberddq072
Pages (from-to)1939-1950
Number of pages12
JournalHuman Molecular Genetics
Issue number10
Publication statusPublished - Feb 16 2010

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology


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