Inhibitors of metabolism rescue cell death in Huntington's disease models.
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.
Varma
Hemant
H
Department of Biological Sciences, Fairchild Center, MC 2406, Columbia University, 1212 Amsterdam Avenue, New York, NY 10027, and Department of Pathology, Massachusetts General Hospital Center for Cancer Research, Charlestown, MA 02129, USA.
Cheng
Richard
R
Voisine
Cindy
C
Hart
Anne C
AC
Stockwell
Brent R
BR
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D004331:Drosophila melanogaster; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006816:Huntington Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009243:NAD / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D015398:Signal Transduction
D017382:Reactive Oxygen Species; D012402:Rotenone; D009243:NAD; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020169:Caspases