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Inhibitors of metabolism rescue cell death in Huntington's disease models

Hemant Varma; Richard Cheng; Cindy Voisine; Anne Hart; Brent R. Stockwell

Title:
Inhibitors of metabolism rescue cell death in Huntington's disease models
Author(s):
Varma, Hemant
Cheng, Richard
Voisine, Cindy
Hart, Anne
Stockwell, Brent R.
Date:
Type:
Articles
Department(s):
Pathology and Cell Biology
Biological Sciences
Volume:
104
Persistent URL:
Book/Journal Title:
Proceedings of the National Academy of Sciences
Publisher:
National Academy of Sciences
Abstract:
Huntington's disease (HD) is a fatal inherited neurodegenerative disorder. HD is caused by polyglutamine expansions in the huntingtin (htt) protein that result in neuronal loss and contribute to HD pathology. The mechanisms of neuronal loss in HD are elusive, and there is no therapy to alleviate HD. To find small molecules that slow neuronal loss in HD, we screened 1,040 biologically active molecules to identify suppressors of cell death in a neuronal cell culture model of HD. We found that inhibitors of mitochondrial function or glycolysis rescued cell death in this cell culture and in in vivo HD models. These inhibitors prevented cell death by activating prosurvival ERK and AKT signaling but without altering cellular ATP levels. ERK and AKT inhibition through the use of specific chemical inhibitors abrogated the rescue, whereas their activation through the use of growth factors rescued cell death, suggesting that this activation could explain the protective effect of metabolic inhibitors. Both ERK and AKT signaling are disrupted in HD, and activating these pathways is protective in several HD models. Our results reveal a mechanism for activating prosurvival signaling that could be exploited for treating HD and possibly other neurodegenerative disorders.
Subject(s):
Nervous system--Degeneration
Cell death
Huntington's disease
Biochemistry
Publisher DOI:
https://doi.org/10.1073/pnas.0704482104
Item views
200
Metadata:
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Suggested Citation:
Hemant Varma, Richard Cheng, Cindy Voisine, Anne Hart, Brent R. Stockwell, , Inhibitors of metabolism rescue cell death in Huntington's disease models, Columbia University Academic Commons, .

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