PUBLICATION

Antioxidants Can Inhibit Basal Autophagy and Enhance Neurodegeneration in Models of Polyglutamine Disease

Authors
Underwood, B.R., Imarisio, S., Fleming, A., Rose, C., Krishna, G., Heard, P., Quick, M., Korolchuk, V.I., Renna, M., Sarkar, S., García-Arencibia, M., O'Kane, C.J., Murphy, M.P., and Rubinsztein, D.C.
ID
ZDB-PUB-100625-16
Date
2010
Source
Human molecular genetics   19(17): 3413-3429 (Journal)
Registered Authors
Fleming, Angeleen
Keywords
none
MeSH Terms
  • Animals
  • Antioxidants/administration & dosage*
  • Autophagy/drug effects*
  • COS Cells
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Drosophila
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Neurodegenerative Diseases/drug therapy*
  • Neurodegenerative Diseases/embryology
  • Neurodegenerative Diseases/metabolism
  • Neurodegenerative Diseases/physiopathology*
  • Oxidative Stress
  • Peptides/metabolism*
  • Reactive Oxygen Species/metabolism
  • Zebrafish
PubMed
20566712 Full text @ Hum. Mol. Genet.
Abstract
Many neurodegenerative diseases exhibit protein accumulation and increased oxidative stress. Therapeutic strategies include clearing aggregate-prone proteins by enhancing autophagy or decreasing oxidative stress with antioxidants. Many autophagy-inducing stimuli increase reactive oxygen species (ROS), raising concerns that the benefits of autophagy up-regulation may be counterbalanced by ROS toxicity. Here we show that not all autophagy inducers significantly increase ROS. However, many antioxidants inhibit both basal and induced autophagy. By blocking autophagy, antioxidant drugs can increase the levels of aggregate-prone proteins associated with neurodegenerative disease. In fly and zebrafish models of Huntington's disease, antioxidants exacerbate the disease phenotype and abrogate the rescue seen with autophagy-inducing agents. Thus, the potential benefits in neurodegenerative diseases of some classes of antioxidants may be compromised by their autophagy-blocking properties.
Genes / Markers
Figures
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Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping