Our studies for the first time unveil a novel microglial ERS-driven inflammatory signaling pathway involving TXNIP and NLRP3 activation in the expression of the neurotoxic microglial activation state in the context of α-synucleinopathy and that inhibition of microglial ERS and the TXNIP/NLRP3 signaling axis may represent a novel and effective therapeutic strategy for PD treatment. The gene discussed is NLRP3; the disease is synucleinopathy.