David Blum, Yijuang Chern, Maria Rosaria Domenici, Luc Buée, Chien-Yu Lin, William Rea, Sergi Ferré, Patrizia Popoli
{"title":"The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease.","authors":"David Blum, Yijuang Chern, Maria Rosaria Domenici, Luc Buée, Chien-Yu Lin, William Rea, Sergi Ferré, Patrizia Popoli","doi":"10.1089/caff.2018.0006","DOIUrl":null,"url":null,"abstract":"<p><p>Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a mutation in the IT15 gene that encodes for the huntingtin protein. Mutated hungtingtin, although widely expressed in the brain, predominantly affects striato-pallidal neurons, particularly enriched with adenosine A<sub>2A</sub> receptors (A<sub>2A</sub>R), suggesting a possible involvement of adenosine and A<sub>2A</sub>R is the pathogenesis of HD. In fact, polymorphic variation in the <i>ADORA2A</i> gene influences the age at onset in HD, and A<sub>2A</sub>R dynamics is altered by mutated huntingtin. Basal levels of adenosine and adenosine receptors are involved in many processes critical for neuronal function and homeostasis, including modulation of synaptic activity and excitotoxicity, the control of neurotrophin levels and functions, and the regulation of protein degradation mechanisms. In the present review, we critically analyze the current literature involving the effect of altered adenosine tone and adenosine receptors in HD and discuss why therapeutics that modulate the adenosine system may represent a novel approach for the treatment of HD.</p>","PeriodicalId":15112,"journal":{"name":"Journal of Caffeine and Adenosine Research","volume":null,"pages":null},"PeriodicalIF":1.7000,"publicationDate":"2018-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049521/pdf/caff.2018.0006.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Caffeine and Adenosine Research","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1089/caff.2018.0006","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"Pharmacology, Toxicology and Pharmaceutics","Score":null,"Total":0}
引用次数: 0
Abstract
Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a mutation in the IT15 gene that encodes for the huntingtin protein. Mutated hungtingtin, although widely expressed in the brain, predominantly affects striato-pallidal neurons, particularly enriched with adenosine A2A receptors (A2AR), suggesting a possible involvement of adenosine and A2AR is the pathogenesis of HD. In fact, polymorphic variation in the ADORA2A gene influences the age at onset in HD, and A2AR dynamics is altered by mutated huntingtin. Basal levels of adenosine and adenosine receptors are involved in many processes critical for neuronal function and homeostasis, including modulation of synaptic activity and excitotoxicity, the control of neurotrophin levels and functions, and the regulation of protein degradation mechanisms. In the present review, we critically analyze the current literature involving the effect of altered adenosine tone and adenosine receptors in HD and discuss why therapeutics that modulate the adenosine system may represent a novel approach for the treatment of HD.
亨廷顿氏病(Huntington's disease,HD)是一种遗传性神经退行性疾病,由编码亨廷丁蛋白的 IT15 基因突变引起。变异的亨廷廷蛋白虽然在大脑中广泛表达,但主要影响纹状体-苍白球神经元,尤其是富含腺苷 A2A 受体(A2AR)的神经元,这表明腺苷和 A2AR 可能参与了 HD 的发病机制。事实上,ADORA2A基因的多态性变异会影响HD的发病年龄,而A2AR的动态变化会因突变的亨廷蛋白而改变。腺苷和腺苷受体的基础水平参与了许多对神经元功能和稳态至关重要的过程,包括突触活动和兴奋毒性的调节、神经营养素水平和功能的控制以及蛋白质降解机制的调节。在本综述中,我们对涉及 HD 中腺苷张力和腺苷受体改变的影响的现有文献进行了批判性分析,并讨论了为什么调节腺苷系统的疗法可能是治疗 HD 的一种新方法。