Parkinsonian toxin-induced oxidative stress inhibits basal autophagy in astrocytes via NQO2/quinone oxidoreductase 2: Implications for neuroprotection

摘要: Oxidative stress (OS) stimulates autophagy in different cellular systems, but it remains controversial if this rule can be generalized. We have analyzed the effect of chronic OS induced by parkinsonian toxin paraquat (PQ) on astrocytoma cells and primary astrocytes, which represent first target neurotoxins brain. PQ decreased basal levels LC3-II LC3-positive vesicles, its colocalization with lysosomal markers, both absence presence chloroquine. This was paralleled increased number size SQSTM1/p62 aggregates. Downregulation also observed chronically exposed to hydrogen peroxide or nonlethal concentrations PQ, associated a reduced astrocyte capability protect dopaminergic from co-cultures. Surprisingly, treatment led inhibition MTOR, activation MAPK8/JNK1 MAPK1/ERK2-MAPK3/ERK1 upregulation BECN1/Beclin 1 expression, all signals typically correlating induction autophagy. Reduction NMDPEF, specific NQO2 inhibitor, not N-acetylcysteine, abrogated inhibitory restored autophagic flux. Activation menadione genetic manipulation expression confirmed role enzyme action did induce NFE2L2/NRF2, when co-administered NMDPEF NFE2L2 activity enhanced SQSTM1-independent fashion. Thus, prolonged astrocytes inhibits LC3 lipidation impairs autophagosome formation flux, spite concomitant several pro-autophagic signals. These findings outline an unanticipated neuroprotective identify novel pharmacological for positive modulation.