ALTERED EXPRESSION AND FUNCTIONALITY OF A2A ADENOSINE RECEPTORS IN HUNTINGTON’S DISEASE AND OTHER POLYGLUTAMINE DISORDERS

Several studies have suggested the possible involvement of A2A adenosine receptors in the pathogenesis of neuronal disorders, including Huntington’s disease. Huntington’s disease is an inherited neurodegenerative disease clinically characterized by motor, cognitive and behavioural impairments. The genetic cause of the disease is the expanded CAG triplet in a gene coding for huntingtin, a protein involved in several physiological processes. Huntington’s disease affects primarly GABAergic neurons in the basal ganglia that express adenosine A2A and dopamine D2 receptors. The present study describes a functional alteration of A2A adenosine receptor in striatal cells engineerized to express full length or truncated, wild type or mutant huntingtin. The data obtained demonstrate that the presence of mutant huntingtin induce an amplification of the transduction signal mediated by adenylyl cyclase and an aberrant coupling of A2A receptor to this transduction pathway. The expression and functionality of A2A adenosine receptor were subsequently evaluated in transgenic mice R6/2, an animal model of Huntington’s disease that express exon 1 of the human huntingtin gene. Saturation binding experiments revealed an increase of A2A receptor levels in striatum of R6/2 mice until 14 post natal days. In addition, also the potency of a typical A2A agonist was increased in striatal membranes of R6/2 mice when compared to wild type mice. The subsequent study aimed the evaluation of the presence and functionality of A2A adenosine receptors in peripheral blood cells from patients affected by Huntington’s disease compared with control subjects. The results revealed a statistically significant increase of the A2A receptor density in platelets, lymphocytes and neutrophils of Huntington’s disease patients and presymptomatic carriers of the mutation when compared to control subjects. In order to verify the specificity of A2A receptor alteration in polyglutamine disease, the same study was conducted in blood cells from patients affected by Spinocerebellar ataxia, characterized by an expanded CAG triplet in the ataxin gene and in patients affected by Friedreich’s ataxia, characterized by an expansion of the GAA triplet. Saturation binding experiments in peripheral blood cells from Spinocerebellar ataxia showed altered A2A binding parameters similar to those obtained in Huntington’s disease patients. In addition, data obtained in Friedreich’s ataxia patients showed affinity and density values for A2A receptors similar to those obtained from control subjects, demonstrating the involvement of the CAG but not of the GAA triplet. Overall these data demonstrate that an aberrant A2A receptor phenotype is present in polyglutamine disorders and this seems to be related with the expanded CAG triplet. The amplification of the signal transduction system of A2A receptors suggests that the use of selective A2A antagonists could be beneficial in the treatment of Huntington’s disease as well as in other related polyglutamine diseases. In addition, the alteration of A2A receptors in peripheral blood cells of patients with polyglutamine diseases suggests that this receptor could be an easily accessible biomarker for the evaluation of the efficacy of potential new therapies.