The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

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 2A receptors (A 2A R), suggesting a possible involvement of adenosine and A 2A R is the pathogenesis of HD. In fact, polymorphic variation in the ADORA2A gene influences the age at onset in HD, and A 2A 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.