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

Elzbieta Janda, Antonella Lascala, Cristina Carresi, Maddalena Parafati, Serafina Aprigliano, Vanessa Russo, Claudia Savoia, Elena Ziviani, Vincenzo Musolino, Federica Morani, Ciro Isidoro, Vincenzo Mollace

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

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

Original languageEnglish
Pages (from-to)1063-1080
Number of pages18
JournalAutophagy
Volume11
Issue number7
DOIs
Publication statusPublished - Jan 1 2015

Fingerprint

Paraquat
Autophagy
Astrocytes
Oxidoreductases
Oxidative Stress
Vitamin K 3
Neuroprotection
benzoquinone
NRH - quinone oxidoreductase2
Astrocytoma
Neurotoxins
Chloroquine
Acetylcysteine
Coculture Techniques
Hydrogen Peroxide
Up-Regulation
Down-Regulation
Pharmacology
Brain
Enzymes

Keywords

  • Astrocytes
  • Macroautophagy
  • NQO2
  • Paraquat
  • Parkinson disease
  • ROS

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Parkinsonian toxin-induced oxidative stress inhibits basal autophagy in astrocytes via NQO2/quinone oxidoreductase 2 : Implications for neuroprotection. / Janda, Elzbieta; Lascala, Antonella; Carresi, Cristina; Parafati, Maddalena; Aprigliano, Serafina; Russo, Vanessa; Savoia, Claudia; Ziviani, Elena; Musolino, Vincenzo; Morani, Federica; Isidoro, Ciro; Mollace, Vincenzo.

In: Autophagy, Vol. 11, No. 7, 01.01.2015, p. 1063-1080.

Research output: Contribution to journalArticle

Janda, E, Lascala, A, Carresi, C, Parafati, M, Aprigliano, S, Russo, V, Savoia, C, Ziviani, E, Musolino, V, Morani, F, Isidoro, C & Mollace, V 2015, 'Parkinsonian toxin-induced oxidative stress inhibits basal autophagy in astrocytes via NQO2/quinone oxidoreductase 2: Implications for neuroprotection', Autophagy, vol. 11, no. 7, pp. 1063-1080. https://doi.org/10.1080/15548627.2015.1058683
Janda, Elzbieta ; Lascala, Antonella ; Carresi, Cristina ; Parafati, Maddalena ; Aprigliano, Serafina ; Russo, Vanessa ; Savoia, Claudia ; Ziviani, Elena ; Musolino, Vincenzo ; Morani, Federica ; Isidoro, Ciro ; Mollace, Vincenzo. / Parkinsonian toxin-induced oxidative stress inhibits basal autophagy in astrocytes via NQO2/quinone oxidoreductase 2 : Implications for neuroprotection. In: Autophagy. 2015 ; Vol. 11, No. 7. pp. 1063-1080.
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AU - Carresi, Cristina

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AU - Savoia, Claudia

AU - Ziviani, Elena

AU - Musolino, Vincenzo

AU - Morani, Federica

AU - Isidoro, Ciro

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