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

TitleAntioxidants can inhibit basal autophagy and enhance neurodegeneration in models of polyglutamine disease.
Publication TypeJournal Article
Year of Publication2010
AuthorsUnderwood, BR, Imarisio, S, Fleming, A, Rose, C, Krishna, G, Heard, P, Quick, M, Korolchuk, VI, Renna, M, Sarkar, S, García-Arencibia, M, O'Kane, CJ, Murphy, MP, Rubinsztein, DC
JournalHum Mol Genet
Volume19
Issue17
Pagination3413-29
Date Published2010 Sep 1
ISSN1460-2083
KeywordsAnimals, Antioxidants, Autophagy, Cercopithecus aethiops, COS Cells, Disease Models, Animal, Drosophila, HeLa Cells, Humans, Mice, Mice, Inbred C57BL, Neurodegenerative Diseases, Oxidative Stress, Peptides, Reactive Oxygen Species, Zebrafish
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.

DOI10.1093/hmg/ddq253
Alternate JournalHum. Mol. Genet.
Citation Key10.1093/hmg/ddq253
PubMed ID20566712
PubMed Central IDPMC2916709
Grant ListG0600194 / / Medical Research Council / United Kingdom
G0901339 / / Medical Research Council / United Kingdom
MC_U105663142 / / Medical Research Council / United Kingdom
/ / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom