Journal Article

Antioxidants can inhibit basal autophagy and enhance neurodegeneration in models of polyglutamine disease

Benjamin R. Underwood, Sara Imarisio, Angeleen Fleming, Claudia Rose, Gauri Krishna, Phoebe Heard, Marie Quick, Viktor I. Korolchuk, Maurizio Renna, Sovan Sarkar, Moisés García-Arencibia, Cahir J. O'Kane, Michael P. Murphy and David C. Rubinsztein

in Human Molecular Genetics

Volume 19, issue 17, pages 3413-3429
Published in print September 2010 | ISSN: 0964-6906
Published online June 2010 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddq253

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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.

Journal Article.  8694 words.  Illustrated.

Subjects: Genetics and Genomics

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