HPRT-deficiency dysregulates cAMP-PKA signaling and phosphodiesterase 10A expression: mechanistic insight and potential target for Lesch-Nyhan Disease?
HPRT-deficiency dysregulates cAMP-PKA signaling and phosphodiesterase 10A expression: mechanistic insight and potential target for Lesch-Nyhan Disease?
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DOI：
10.1371/journal.pone.0063333
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Barron N
中科院分区：
文献类型：
--
作者：
Guibinga GH;Murray F;Barron N
莱-尼二氏病（LND）是编码嘌呤代谢酶次黄嘌呤鸟嘌呤磷酸核糖转移酶（HPRT）的X连锁基因突变的结果。LND引起严重的神经系统异常，包括精神发育迟滞、肌张力障碍、舞蹈病、锥体束征和自我伤害的强迫性和攻击性行为。LND的神经系统表型已被证明反映了基底神经节中异常的多巴胺能信号传导，然而几乎没有数据将嘌呤代谢缺陷与神经相关异常相关联。在本研究中，我们发现HPRT缺陷的神经元细胞系具有减少的CREB（cAMP反应元件结合蛋白）表达和细胞内环AMP（cAMP），这与衰减的CREB依赖性转录活性和减少的蛋白激酶A（PKA）底物如突触蛋白（p-syn I）的磷酸化相关。有趣的是，我们发现磷酸二酯酶10A（PDE 10A）在HPRT缺陷细胞系中的表达增加，并且PDE 10抑制剂罂粟碱和PDE 10A siRNA恢复cAMP/PKA信号传导。此外，在突变细胞中HPRT表达的重建部分增加cAMP信号突触蛋白磷酸化。总之，我们的数据表明，HPRT缺陷改变cAMP/PKA信号通路，这部分是由于PDE 10A表达和活性增加。这些发现表明了对LND可能原因的机制性见解，并突出了PDE 10A作为这种难治性神经系统疾病的可能治疗靶点。
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.
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