The role of P2Y1 receptor in Parkinsons Disease

Abstract

Parkinson's Disease is a highly prevalent neurodegenerative illness which presents the death of dopaminergic neurons, motor dysfunctions, constipation, and comorbidities as neuropsychiatric disorders. These features are primarily responsible for incapacitation and loss of life quality. Microglial cells and astrocytes control the lesion, due to phagocytic capability, neurotrophic factors release, and glial scar formation which confine the injured area and avoid the spreading of inflammation. The discovery of adult neurogenesis leads to a therapeutic approach for diseases with neuronal death. For Parkinson's Disease, this approach seemed even more relevant, once neural stem cells of subventricular zone can migrate to the nigrostriatal pathway, where presents loss of dopaminergic neurons. It was already shown that the purinergic P2Y1 receptor promotes an increase in intracellular calcium waves, microglial cells migration, astrocytes reactivity, modulation of cytokines and chemokines, neural stem cells proliferation and migration, and increase dopamine release. The same mechanisms were described in the control of adult neurogenesis or neuroregeneration processes. There is a clear overlap between the modulatory mechanisms of P2Y1 receptor and the molecular features of Parkinson's Disease patients although no studies are verifying this relation. This project proposal has as main goal to verify the participation of P2Y1 in Parkinson's Disease. We will analyze the expression of P2Y1 receptor in post-mortem tissue of patients with Parkinson as well as perform the lesion in the striatum by 6-hydroxydopamine (6-OHDA) animal model. To confer more translation to our project, we will characterize the intranasal administration of the selective agonist of P2Y1 receptor, MRS2365. Regarding the 6-OHDA model, the main aim is to evaluate the participation of P2Y1 receptor upon the glial scar and neural stem cells recruitment of the subventricular zone to the lesioned striatum. Also, we will use the primary culture approach of adult neural stem cells of subventricular zone to analyze the cellular and molecular differences of neurospheres from treated and non-treated rats with MRS2365 after the 6-OHDA lesion. Our preliminary results showed that dopaminergic neurogenesis is the main pathway responsible for the pathogenesis of Parkinson's Disease in the substantia nigra. Also, the animal model of 6-OHDA lesion in the nigrostriatal pathway seems to induce a decrease in the P2Y1 receptor expression. These results indicate that P2Y1 receptor may exert a potential therapeutic role in neuroregeneration. (AU)