Thus, our observations raise the possibility that initial activation of the unfolded protein response (UPR) in α-synucleinopathy might have a neuroprotective role to compensate for the accumulation of misfolded proteins; however, persistent ERS may overwhelm the cellular antioxidant machinery via PKCδ and TXNIP upregulation eventually leading to the loss of nigral DAergic neurons. The gene discussed is PRKCD; the disease is synucleinopathy.