Targeting microglial NLRP3 in the SNc region as a promising disease-modifying therapy for Parkinson's disease

Abstract

Introduction: Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic (DA) neurons. Accumulating evidence has shown that activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome is an early and cardinal feature in PD progression. Nevertheless, little is known about the effect of NLRP3 in the substantia nigra pars compacta (SNc) on DA neurodegeneration.

Methods and results: In the present study, we constructed NLRP3 interference sequences wrapped by lentivirus (LV3-siNlrp3) to facilitate NLRP3 knockdown in the SNc region by intracerebral stereotactic injection. Then, we explored the effects of NLPR3 knockdown on PD pathologies via behavioral monitoring, immunohistochemistry and western blot analysis in acute 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) mouse model. Moreover, we performed in vitro experiments to investigate the effect of microglial NLRP3 knockdown on DA neuron survival in the context of 1-methyl-4-phenylpyridinium (MPP⁺ ) stimulation. Our results demonstrated that NLRP3 knockdown in the SNc region significantly improved MPTP-induced dyskinesia, DA neuronal loss and microglia activation in vivo. Meanwhile, knockdown of microglial NLRP3 attenuated MPP⁺ -induced DA neuronal damage in an indirect coculture system in which neurons were cultured in microglial conditional medium. Cumulatively, these data reveal that microglial NLRP3 located in the SNc region is detrimental to DA neurons survival, and knockdown of microglial NLRP3 is a potential strategy to rescue DA neurons in the progression of PD.

Conclusions: This work demonstrates the role of NLRP3 in PD pathogenesis via microglia-neuron communication, and sheds light on targeting microglial NLRP3 to develop disease-modifying therapy for PD.

Keywords: NLRP3; Parkinson's disease; disease-modifying therapy; dopaminergic neuron; microglia.