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

@entity6453 @entity64277 @entity66 @entity8197 @entity16402 @entity3963 @entity898 @entity191 @entity273 @entity13791 @entity8783 @entity816 @entity4675 @entity19213 @entity21684 @entity12206 @entity503
UNASSIGNED: @entity66 ( @entity66 ) stimulates autophagy in different cellular systems, but it remains controversial if this rule can be generalized. We have analyzed the effect of chronic @entity66 induced by the @entity191 toxin @entity6453 (PQ) on autophagy in @entity816 cells and primary astrocytes, which represent the first cellular target of neurotoxins in the brain. PQ decreased the basal levels of @entity21684 -II and @entity21684 -positive vesicles, and its colocalization with lysosomal markers, both in the absence and presence of @entity503 . This was paralleled by increased number and size of @entity16402 / @entity16402 aggregates. Downregulation of autophagy was also observed in cells chronically exposed to @entity273 or nonlethal concentrations of PQ, and it was associated with a reduced astrocyte capability to protect dopaminergic cells from @entity66 in co-cultures. Surprisingly, PQ treatment led to inhibition of @entity19213 , activation of @entity4675 / @entity4675 and @entity3963 / @entity3963 - @entity12206 / @entity12206 and upregulation of @entity8783 / @entity8783 expression, all signals typically correlating with induction of autophagy. Reduction of @entity66 by NMDPEF, a specific @entity64277 inhibitor, but not by @entity898 , abrogated the inhibitory effect of PQ and restored autophagic flux. Activation of @entity64277 by PQ or @entity8197 and genetic manipulation of its expression confirmed the role of this enzyme in the inhibitory action of PQ on autophagy. PQ did not induce @entity13791 / @entity13791 , but when it was co-administered with NMDPEF @entity13791 activity was enhanced in a @entity16402 -independent fashion. Thus, a prolonged @entity66 in astrocytes inhibits @entity21684 lipidation and impairs autophagosome formation and autophagic flux, in spite of concomitant activation of several pro-autophagic signals. These findings outline an unanticipated neuroprotective role of astrocyte autophagy and identify in @entity64277 a novel pharmacological target for its positive modulation.
