Autophagy and neuroprotection in astrocytes exposed to 6-hydroxydopamine is negatively regulated by NQO2: a potential novel target in Parkinson’s disease.

Abstract

Abstract Dopaminergic degeneration is a central feature of Parkinson’s disease (PD), but glial dysfunction may accelerate or trigger neuronal death. In fact, astrocytes play a key role in maintenance of the blood-brain barrier and detoxification. 6-hydroxydopamine (6OHDA) is used to induce PD in rodent models due to its specific toxicity to dopaminergic neurons, but its effect on astrocytes has been poorly investigated. Here, we show that 6OHDA dose-dependently impairs autophagy in human U373 and primary murine astrocytes in the absence of cell death. LC3II downregulation was observed 6 to 48 hours after treatment. Interestingly, 6OHDA enhanced NRH:quinone oxidoreductase 2 (NQO2) expression and activity in U373 cells, even if 6OHDA is not its substrate. The autophagic flux was restored by inhibition of NQO2 with S29434, which correlated with a partial reduction of oxidative stress in response to 6OHDA in human and murine astrocytes. NQO2 inhibition also increased neuroprotective capability of U373 cells, since S29434 protected dopaminergic SHSY5Y cells from 6OHDA-induced cell death when co-cultured with astrocytes. Silencing of NQO2 attenuated toxic effects of 6OHDA on autophagy. Finally, the analysis of Gene Expression Ominibus datasets showed elevated NQO2 gene expression in the blood cells of early-stage PD patients. These data support a toxifying function of NQO2 in dopaminergic degeneration via negative regulation of autophagy and neuroprotection in astrocytes, suggesting a novel pharmacological target in PD.