Probing the role of Free-Fatty Acid Receptor-4 (FFA4) as novel target for Parkinson’s Disease: FFA4 agonists increase dopamine synthesis and reduce 6-OHDA-induced cell death

Abstract ID 92499 Poster Board 148 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 and neuroinflammation in the microenvironment of the substantia nigra play important roles in facilitating DAergic cell death. Here, we show that agonism of the G protein-coupled Free-Fatty Acid Receptor-4 (FFA4), endogenously expressed on DA-synthesizing PC12 cells and in rat striatum, with the endogenous FFA agonist docosahexaenoic acid (DHA) or the synthetic FFA4 agonist TUG-891, activates the DA-synthesizing enzyme tyrosine hydroxylase (TH), and also protects 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 DHA and TUG-891 increase DA concentrations in the 6-OHDA rat model of PD, and taken together, these findings suggest that targeting of FFA4 could increase DA synthesis for symptom control, and also alleviate oxidative stress and neuroinflammation that contribute to disease progression. Funded by NIH/NINDS NS095239