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Parkinsonian toxin-induced oxidative stress inhibits basal autophagy in astrocytes via NQO2/quinone oxidoreductase 2: Implications for neuroprotection.
Autophagy. 2015; 11(7):1063-80.A

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.

Authors+Show Affiliations

a Department of Health Sciences; University "Magna Graecia"; Campus Germaneto ; Catanzaro , Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26046590

Citation

Janda, Elzbieta, et al. "Parkinsonian Toxin-induced Oxidative Stress Inhibits Basal Autophagy in Astrocytes Via NQO2/quinone Oxidoreductase 2: Implications for Neuroprotection." Autophagy, vol. 11, no. 7, 2015, pp. 1063-80.
Janda E, Lascala A, Carresi C, et al. Parkinsonian toxin-induced oxidative stress inhibits basal autophagy in astrocytes via NQO2/quinone oxidoreductase 2: Implications for neuroprotection. Autophagy. 2015;11(7):1063-80.
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, 11(7), 1063-80. https://doi.org/10.1080/15548627.2015.1058683
Janda E, et al. Parkinsonian Toxin-induced Oxidative Stress Inhibits Basal Autophagy in Astrocytes Via NQO2/quinone Oxidoreductase 2: Implications for Neuroprotection. Autophagy. 2015;11(7):1063-80. PubMed PMID: 26046590.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Parkinsonian toxin-induced oxidative stress inhibits basal autophagy in astrocytes via NQO2/quinone oxidoreductase 2: Implications for neuroprotection. AU - Janda,Elzbieta, AU - Lascala,Antonella, AU - Carresi,Cristina, AU - Parafati,Maddalena, AU - Aprigliano,Serafina, AU - Russo,Vanessa, AU - Savoia,Claudia, AU - Ziviani,Elena, AU - Musolino,Vincenzo, AU - Morani,Federica, AU - Isidoro,Ciro, AU - Mollace,Vincenzo, PY - 2015/6/6/entrez PY - 2015/6/6/pubmed PY - 2016/4/19/medline KW - AVs, autophagic vacuoles KW - Ab, antibody KW - BNAH, benzyldihydronicotinamide riboside KW - CA-DCF-DA, 5(6)-carboxy-2′,7′ dichlorofluorescein diacetate KW - CQ, chloroquine KW - DMEM, Dulbecco's modified Eagle's medium KW - DMSO, dimethyl sulfoxide KW - FACS, flow cytometry KW - GFAP, glial fibrillary acidic protein KW - GFP, green fluorescent protein KW - K3, menadione KW - MAPK, mitogen-activated protein kinase KW - MFI, mean fluorescence intensity KW - MPTP, 1-methyl 4-phenyl 1,2,3,6-tetraidro-piridine KW - MitoSOX, 3,8-phenanthridinediamine, 5-(6′-triphenylphosphoniumhexyl)-5,6 dihydro-6-phenyl KW - NFE2L2, nuclear factor, erythroid 2-like 2 KW - NMDPEF, N-[2-(2-methoxy-6H-dipyrido[2,3-a:3,2-e]pyrrolizin-11-yl)ethyl]-2-furamide] KW - NQO2 KW - OS, oxidative stress KW - PBS, phosphate-buffered saline KW - PQ, paraquat KW - ROS KW - ROS, reactive oxygen species KW - RT, room temperature KW - SN, substantia nigra KW - TTBS, Tween-Tris buffered saline KW - WB, western blotting KW - astrocytes KW - macroautophagy KW - p-, phosphorylated KW - paraquat KW - parkinson disease KW - shRNA, short harpin ribonucleic acid KW - siRNA, small interfering ribonucleic acid SP - 1063 EP - 80 JF - Autophagy JO - Autophagy VL - 11 IS - 7 N2 - 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. SN - 1554-8635 UR - https://www.unboundmedicine.com/medline/citation/26046590/Parkinsonian_toxin_induced_oxidative_stress_inhibits_basal_autophagy_in_astrocytes_via_NQO2/quinone_oxidoreductase_2:_Implications_for_neuroprotection_ L2 - https://www.tandfonline.com/doi/full/10.1080/15548627.2015.1058683 DB - PRIME DP - Unbound Medicine ER -