title: Antioxidants can inhibit basal autophagy and enhance neurodegeneration in models of polyglutamine disease.
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.
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Underwood
authors.forename: Sara
authors.initials: S
authors.lastname: Imarisio
authors.forename: Angeleen
authors.initials: A
authors.lastname: Fleming
authors.forename: Claudia
authors.initials: C
authors.lastname: Rose
authors.forename: Gauri
authors.initials: G
authors.lastname: Krishna
authors.forename: Phoebe
authors.initials: P
authors.lastname: Heard
authors.forename: Marie
authors.initials: M
authors.lastname: Quick
authors.forename: Viktor I
authors.initials: VI
authors.lastname: Korolchuk
authors.forename: Maurizio
authors.initials: M
authors.lastname: Renna
authors.forename: Sovan
authors.initials: S
authors.lastname: Sarkar
authors.forename: Moisés
authors.initials: M
authors.lastname: García-Arencibia
authors.forename: Cahir J
authors.initials: CJ
authors.lastname: O'Kane
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D001343:Autophagy / Q000187:drug effects*; D019556:COS Cells; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004330:Drosophila; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000196:embryology / Q000378:metabolism / Q000503:physiopathology*; D018384:Oxidative Stress; D010455:Peptides / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015027:Zebrafish
chemical_list: D000975:Antioxidants; D010455:Peptides; D017382:Reactive Oxygen Species; C097188:polyglutamine