Probing The Role of Free Fatty Acid Receptor 4 As A Novel Potential Therapeutic Target In Parkinson's Disease

Abstract

Parkinson’s Disease (PD) is a debilitating neurodegenerative disease that affects over 10 million people worldwide, with 90,000 newly diagnosed patients each year in the US alone. Patients affected by this disease face a decreased quality of life due to the characteristic motor symptoms, together with burdensome cognitive as well as peripheral symptoms. These symptoms are known to arise due to death of dopamine (DA) producing neurons of the substantia nigra pars compacta in the basal ganglia, and for nearly 60 years, pharmacological treatment of PD has relied on treatment with levodopa or DA receptor agonists, which act to improve the DAergic deficiency, but do not alter the underlying neurodegeneration and disease progression. Though the absolute etiology of PD remains unclear, it is known that oxidative stress, neuroinflammation, and aggregation of oligomers of alpha synuclein in the microenvironment of the substantia nigra play important roles in facilitating DAergic cell death. Our study examined the capacity of G protein-coupled Free-Fatty Acid Receptor-4 (FFA4) signaling to regulate cell toxicity induced by 6-OHDA-mediated ROS generation, NF-κB-mediated neuroinflammation, and alpha synuclein-related cell death. Here, we show that agonism of FFA4, endogenously expressed on DA-synthesizing PC-12 cells and in rat striatal minces, with the endogenous FFA agonist docosahexaenoic acid (DHA) and the synthetic FFA4 agonist TUG-891, activate the DA-synthesizing enzyme tyrosine hydroxylase (TH) and also protect from 6- hydroxydopamine (6-OHDA)-induced cell death. Furthermore, FFA4 agonism reduces 6-OHDA-induced ROS generation and downstream NF-κB activity. Our results also show that TUG-891 increases DA concentrations in the 6-OHDA rat model of PD. Taken together, these findings suggest that targeting of FFA4 could increase DA synthesis for symptom control and alleviate oxidative stress and neuroinflammation that contribute to disease progression.