Adenosine A1-A2A Receptor Heteromer as a Possible Target for Early-Onset Parkinson's Disease

EOPD patients generally display a slower progression of the disease and present a better response to dopaminergic treatments; however, they may finally develop a full PD symptomatology (i.e., bradykinesia, resting tremor, muscular rigidity and postural instability, drug-induced dyskinesia; Olgiati et al., 2016). [...]although genetic studies have provided some information about the main genes involved, epidemiological data showed that behavioral and environmental factors play a key role in the pathogenesis and progression of PD (Puschmann, 2013; Ascherio and Schwarzschild, 2016). [...]A1R is markedly expressed in the basal ganglia. [...]A1R can be found in the major striatal neuronal population, the GABAergic medium-sized spiny neurons (MSNs; Ferré et al., 1996), together with the expression in the cortico-thalamic glutamatergic afferent fibers. [...]low to moderate extracellular adenosine concentrations (homeostatic basal levels) mostly stimulate A1R, since it displays higher affinity for adenosine compared to A2AR, and a net inhibition of glutamate release is achieved (Figure 1). [...]managing the disturbance of the adenosine switch mechanism regulating glutamatergic striatal innervation (caused either by a direct ADORA1 mutation or mutations affecting A1R/A2AR heteromers function), may help to restore the normal functioning of the basal ganglia.