The Adenosine A\(_{2A}\) Receptor and Olfactory Dysfunction in Parkinson’s Disease

Abstract

Hyposmia and anosmia (the partial or complete loss of the sense of smell, respectively) is widespread in age-related neurodegenerative diseases, including Parkinson’s disease (PD), the most common neurodegenerative movement disorder. There is specific expression of the G protein-coupled receptor, the adenosine A\(_{2A}\) receptor (A\(_{2A}\)R), in the striatum, a region of the brain that supports the control of movement and in the olfactory bulb (OB), the first relay station in the olfactory system. Thus, olfactory and motor dysfunction may share the same molecular substrate. Of particular interest are reports that deficient olfaction (the sense of smell) predates the motor dysfunction that characterizes PD by several years and even has a greater incidence in PD patients than motor symptoms. Furthermore, the OB is an induction site for the proteopathy that infiltrates the motor complex and cortical regions in later stages of the disease. Despite the prevalence and precedence of olfactory dysfunction over motor dysfunction, however, there has been a myopic focus on the latter, especially with respect to the treatment of motor symptoms by blockade of the A\(_{2A}\)R. Moreover, antagonism of the receptor has also been shown to prevent the loss of neurons in the motor complex and may even reduce the risk for PD. Still it is not known whether conditional inactivation of the A\(_{2A}\)R in the OB would recover olfactory function in a model of PD. Additionally, the potential impact of such inactivation on the progression of alpha-synuclein pathology in an animal model of PD is as enigmatic. We review the pathophysiological basis of motor dysfunction in PD, the capacity of caffeine to prevent and treat PD, and the complex intersection of PD, olfaction, and the A\(_{2A}\)R. We also propose an experimental strategy; specifically, for the analysis of olfactory sensitivity and discrimination in non-transgenic, wild-type, mice that will be given an intrabulbar injection of misfolded alpha-synuclein and then undergo conditional inactivation of the A\(_{2A}\)R in the OB priorly. The methodological approach we describe includes immunohistochemistry and behavioral assays for olfaction, the results of which may lay the foundation for future investigation of the role of the A\(_{2A}\)R in olfactory dysfunction in PD and in the progression of the proteopathy manifest in PD. The ultimate goals of the proposed research are to clarify the extent to which inactivation of the A\(_{2A}\)R may delay the onset or progression of PD and to elucidate the cryptic pathophysiology of olfactory dysfunction in PD as well as a large, albeit select, group of neurodegenerative disorders of the brain.