title: HPRT-deficiency dysregulates cAMP-PKA signaling and phosphodiesterase 10A expression: mechanistic insight and potential target for Lesch-Nyhan Disease?
abstract: 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.
authors.affiliation: Department of Pediatrics, Division of Genetics, University of California San Diego, School of Medicine, La Jolla, California, USA. gguibing@ucsd.edu
authors.forename: Ghiabe-Henri
authors.initials: GH
authors.lastname: Guibinga
authors.forename: Fiona
authors.initials: F
authors.lastname: Murray
authors.forename: Nikki
authors.initials: N
authors.lastname: Barron
mesh_terms: D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D055785:Gene Knockdown Techniques; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000172:deficiency* / Q000235:genetics; D007926:Lesch-Nyhan Syndrome / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics; D058990:Molecular Targeted Therapy; D010641:Phenotype; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016704:Synapsins / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D016704:Synapsins; D000242:Cyclic AMP; D007041:Hypoxanthine Phosphoribosyltransferase; D017868:Cyclic AMP-Dependent Protein Kinases; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases