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.
Citation
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. (2010) Antioxidants Can Inhibit Basal Autophagy and Enhance Neurodegeneration in Models of Polyglutamine Disease. Human molecular genetics. 19(17):3413-3429.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping