Antioxidants can inhibit basal autophagy and enhance neurodegeneration in models of polyglutamine disease.
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.
Underwood
Benjamin R
BR
Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
Imarisio
Sara
S
Fleming
Angeleen
A
Rose
Claudia
C
Krishna
Gauri
G
Heard
Phoebe
P
Quick
Marie
M
Korolchuk
Viktor I
VI
Renna
Maurizio
M
Sarkar
Sovan
S
García-Arencibia
Moisés
M
O'Kane
Cahir J
CJ
Murphy
Michael P
MP
Rubinsztein
David C
DC
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
D000975:Antioxidants; D010455:Peptides; D017382:Reactive Oxygen Species; C097188:polyglutamine