PMID- 23997112
OWN - NLM
STAT- MEDLINE
DCOM- 20140701
LR  - 20230815
IS  - 1096-0929 (Electronic)
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 136
IP  - 1
DP  - 2013 Nov
TI  - Impairment of Atg5-dependent autophagic flux promotes paraquat- and MPP(+)-induced 
      apoptosis but not rotenone or 6-hydroxydopamine toxicity.
PG  - 166-82
LID - 10.1093/toxsci/kft188 [doi]
AB  - Controversial reports on the role of autophagy as a survival or cell death 
      mechanism in dopaminergic cell death induced by parkinsonian toxins exist. We 
      investigated the alterations in autophagic flux and the role of autophagy protein 
      5 (Atg5)-dependent autophagy in dopaminergic cell death induced by parkinsonian 
      toxins. Dopaminergic cell death induced by the mitochondrial complex I inhibitors 
      1-methyl-4-phenylpyridinium (MPP(+)) and rotenone, the pesticide paraquat, and the 
      dopamine analog 6-hydroxydopamine (6-OHDA) was paralleled by increased 
      autophagosome accumulation. However, when compared with basal autophagy levels 
      using chloroquine, autophagosome accumulation was a result of impaired autophagic 
      flux. Only 6-OHDA induced an increase in autophagosome formation. Overexpression 
      of a dominant negative form of Atg5 increased paraquat- and MPP(+)-induced cell 
      death. Stimulation of mammalian target of rapamycin (mTOR)-dependent signaling 
      protected against cell death induced by paraquat, whereas MPP(+)-induced toxicity 
      was enhanced by wortmannin, a phosphoinositide 3-kinase class III inhibitor, 
      rapamycin, and trehalose, an mTOR-independent autophagy activator. Modulation of 
      autophagy by either pharmacological or genetic approaches had no effect on 
      rotenone or 6-OHDA toxicity. Cell death induced by parkinsonian neurotoxins was 
      inhibited by the pan caspase inhibitor (Z-VAD), but only caspase-3 inhibition was 
      able to decrease MPP(+)-induced cell death. Finally, inhibition of the lysosomal 
      hydrolases, cathepsins, increased the toxicity by paraquat and MPP(+), supporting a 
      protective role of Atg5-dependent autophagy and lysosomes degradation pathways on 
      dopaminegic cell death. These results demonstrate that in dopaminergic cells, 
      Atg5-dependent autophagy acts as a protective mechanism during apoptotic cell 
      death induced by paraquat and MPP(+) but not during rotenone or 6-OHDA toxicity.
FAU - Garcia-Garcia, Aracely
AU  - Garcia-Garcia A
AD  - * Redox Biology Center.
FAU - Anandhan, Annandurai
AU  - Anandhan A
FAU - Burns, Michaela
AU  - Burns M
FAU - Chen, Han
AU  - Chen H
FAU - Zhou, You
AU  - Zhou Y
FAU - Franco, Rodrigo
AU  - Franco R
LA  - eng
GR  - P20RR17675/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130831
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (ATG5 protein, human)
RN  - 0 (Autophagy-Related Protein 5)
RN  - 0 (Caspase Inhibitors)
RN  - 0 (Enzyme Activators)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 03L9OT429T (Rotenone)
RN  - 8HW4YBZ748 (Oxidopamine)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.- (Cathepsins)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (Caspase 3)
RN  - PLG39H7695 (Paraquat)
RN  - R865A5OY8J (1-Methyl-4-phenylpyridinium)
SB  - IM
MH  - 1-Methyl-4-phenylpyridinium/*toxicity
MH  - Apoptosis/*drug effects
MH  - Autophagy-Related Protein 5
MH  - Caspase 3/metabolism
MH  - Caspase Inhibitors/pharmacology
MH  - Cathepsins/antagonists & inhibitors/metabolism
MH  - Cell Line, Tumor
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Activation
MH  - Enzyme Activators/pharmacology
MH  - Humans
MH  - Microtubule-Associated Proteins/genetics/*metabolism
MH  - Neurons/*drug effects/metabolism/pathology
MH  - Oxidopamine/*toxicity
MH  - Paraquat/*toxicity
MH  - Phosphatidylinositol 3-Kinase/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Rotenone/*toxicity
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Transfection
PMC - PMC3829573
OTO - NOTNLM
OT  - 6-hydroxydopamine
OT  - Atg5
OT  - MPP+
OT  - Parkinson's disease.
OT  - apoptosis
OT  - autophagy
OT  - cathepsins
OT  - neurodegeneration
OT  - paraquat
OT  - rotenone
EDAT- 2013/09/03 06:00
MHDA- 2014/07/02 06:00
PMCR- 2014/11/01
CRDT- 2013/09/03 06:00
PHST- 2013/09/03 06:00 [entrez]
PHST- 2013/09/03 06:00 [pubmed]
PHST- 2014/07/02 06:00 [medline]
PHST- 2014/11/01 00:00 [pmc-release]
AID - kft188 [pii]
AID - 10.1093/toxsci/kft188 [doi]
PST - ppublish
SO  - Toxicol Sci. 2013 Nov;136(1):166-82. doi: 10.1093/toxsci/kft188. Epub 2013 Aug 
      31.