HPRT-Deficiency Dysregulates cAMP-PKA Signaling and Phosphodiesterase 10A Expression: Mechanistic Insight and Potential Target for Lesch-Nyhan Disease?

Ghiabe-Henri Guibinga, Fiona Murray, Nikki Barron

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18 Citations (Scopus)
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Lesch-Nyhan Disease (LND) is the result of mutations in the X-linked gene encoding the purine metabolic enzyme, hypoxanthine guanine phosphoribosyl transferase (HPRT). LND gives rise to severe neurological anomalies including mental retardation, dystonia, chorea, pyramidal signs and a compulsive and aggressive behavior to self injure. The neurological phenotype in LND has been shown to reflect aberrant dopaminergic signaling in the basal ganglia, however there are little data correlating the defect in purine metabolism to the neural-related abnormalities. In the present studies, we find that HPRT-deficient neuronal cell lines have reduced CREB (cAMP response element-binding protein) expression and intracellular cyclic AMP (cAMP), which correlates with attenuated CREB-dependent transcriptional activity and a reduced phosphorylation of protein kinase A (PKA) substrates such as synapsin (p-syn I). Of interest, we found increased expression of phosphodiesterase 10A (PDE10A) in HPRT-deficient cell lines and that the PDE10 inhibitor papaverine and PDE10A siRNA restored cAMP/PKA signaling. Furthermore, reconstitution of HPRT expression in mutant cells partly increased cAMP signaling synapsin phosphorylation. In conclusion, our data show that HPRT-deficiency alters cAMP/PKA signaling pathway, which is in part due to the increased of PDE10A expression and activity. These findings suggest a mechanistic insight into the possible causes of LND and highlight PDE10A as a possible therapeutic target for this intractable neurological disease.

Original languageEnglish
Article numbere63333
Pages (from-to)1-11
Number of pages11
JournalPloS ONE
Issue number5
Publication statusPublished - 14 May 2013

Bibliographical note

The authors thank Dr. Hyder Jinnah from Emory University School of Medicine for providing us with MN9D cells. The authors also thank Dr. Atsushi Miyanohara, Director of the vector development laboratory from the Department of Pediatrics, UCSD Gene Therapy Program for the preparation of viral vectors.

Funding: This work is supported by a grant from DK082840 from the National Institute of Health, USA, and by a research grant from the University of California San Diego Academic Senate. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


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