GPR40 agonist ameliorates neurodegeneration and motor impairment by regulating NLRP3 inflammasome in Parkinson’s disease animal models

Parkinson's disease (PD) is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra (SN) and accumulation of intracellular α-synuclein (ɑ-syn) aggregates known as Lewy bodies and Lewy neurites. Levels of polyunsaturated fatty acids (PUFAs) have previously been shown to be reduced in the SN of PD patients. G protein-coupled receptor 40 (GPR40) serves as a receptor for PUFAs, playing a role in neurodevelopment and neurogenesis. Additionally, GPR40 has been implicated in several neuropathological conditions, such as apoptosis and inflammation, suggesting its potential as a therapeutic target in PD. In this study, we investigated the neuroprotective effects of the GPR40 agonist, TUG469 in PD models. Our results demonstrated that TUG469 reduces the neurotoxicity induced by 6-OHDA in SH-SY5Y cells. In 6-OHDA-induced PD model mice, TUG469 treatment improved motor impairment, preserved dopaminergic fibers and cell bodies in the striatum (ST) or SN, and attenuated 6-OHDA-induced microgliosis and astrogliosis in the brain. Furthermore, in a PD model involving the injection of mouse ɑ-syn fibrils into the brain (mPFFs-PD model), TUG469 treatment reduced the levels of pSer129 ɑ-syn, and decreased microgliosis and astrogliosis. Our investigation also revealed that TUG469 modulates inflammasome activation, apoptosis, and autophagy in the 6-OHDA-PD model, as evidenced by the results of RNA-seq and western blotting analyses. In summary, our findings highlight the neuroprotective effects of GPR40 agonists on dopaminergic neurons and their potential as therapeutic agents for PD. These results underscore the importance of targeting GPR40 in PD treatment, particularly in mitigating neuroinflammation and preserving neuronal integrity. ● GPR40 played a role in preserving cell viability in 6-OHDA-treated cell lines. ● GPR40 agonist improved behavioral deficits and exhibited neuroprotective effects in the 6-OHDA PD mouse model. ● GPR40 agonist attenuated Lewy body (LB) formation and propagation of ɑ-synuclein in the mPFFs-induced PD mouse model. ● GPR40 agonist inhibited microgliosis and astrogliosis in both the 6-OHDA and mPFFs-induced PD mouse models. ● GPR40 agonists regulate the NLRP3 inflammasome, MAPK activation, and autophagy-related genes.