Agonism of FFA4/GPR120 activates tyrosine hydroxylase and confers neuroprotection from 6-OHDA-induced cytotoxicity in PC12 cells and in a rat 6-OHDA model of Parkinson’s disease

Free-fatty acid receptor 4 (FFA4/GPR120), a G-protein-coupled receptor activated by medium to long-chain free-fatty acids (FFA) including ω-3 polyunsaturated fatty acids, regulates many metabolic and anti-inflammatory processes, and has also been linked to diverse neurophysiological functions. Here, we investigated the expression and functional role of FFA4 in dopaminergic systems using PC12 cells, rat striatal tissue, and an in vivo 6-hydroxydopamine (6-OHDA) model of Parkinson's disease (PD). FFA4 mRNA and protein were expressed in rat caudate-putamen and colocalized with tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis. Agonism of FFA4 by the endogenous agonist docosahexaenoic acid (DHA) or the selective synthetic agonist TUG-891 significantly increased phosphorylation of TH-Ser⁴⁰ in PC12 cells and rat striatal minces, without elevating cAMP, suggesting non-canonical signaling of FFA4 to TH. In PC12 cells, TUG-891 attenuated 6-OHDA-induced cytotoxicity in a concentration-dependent manner, concomitant with reductions in reactive oxygen species (ROS) generation and NF-κB transcriptional activity, effects that were reversed by the FFA4 antagonist AH-7614. In an in vivo rat 6-OHDA model of PD, TUG-891 administration significantly mitigated apomorphine-induced rotational asymmetry and motor deficits in 6-OHDA-lesioned rats, while preserving striatal TH immunoreactivity. These findings identify FFA4 as a novel modulator of dopaminergic neuron integrity that may operate through antioxidant and anti-inflammatory signals to preserve cell function, warranting further exploration of FFA4 in dopaminergic degeneration and PD.