ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington's disease.
Huntington's disease (HD) is an inherited, progressive and ultimately fatal neurodegenerative disorder that is characterized by psychiatric, cognitive and motor symptoms. Among the pathways implicated in HD are those involving mitogen-activated protein kinase signaling and particularly the Ras-extracellular signal-regulated kinase (ERK) cascade. Studies in both cells and animal models suggest that ERK activation might provide a novel therapeutic target for the treatment of HD but compounds that specifically activate ERK are few. To test the hypothesis that pharmaceutical activation of ERK might be protective for HD, a polyphenol, fisetin, which was previously shown to activate the Ras-ERK cascade, was tested in three different models of HD: PC12 cells expressing mutant Httex1 under the control of an inducible promoter, Drosophila expressing mutant Httex1 and the R6/2 mouse model of HD. The results indicate that fisetin can reduce the impact of mutant huntingtin in each of these disease models. Prompted by this observation, we determined that the related polyphenol, resveratrol, also activates ERK and is protective in HD models. Notably, although more than a dozen small molecule inhibitors of ERK activation are in clinical trials, very few small molecule activators of ERK signaling are reported. Thus, fisetin, resveratrol and related compounds might be useful for the treatment of HD by virtue of their unique ability to activate ERK.
Maher
Pamela
P
Department of Cellular Neurobiology, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. pmaher@salk.edu
Dargusch
Richard
R
Bodai
Laszlo
L
Gerard
Paul E
PE
Purcell
Judith M
JM
Marsh
J Lawrence
JL
D000818:Animals; D004195:Disease Models, Animal; D004330:Drosophila / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics* / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D018628:Gene Dosage / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000201:enzymology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics; D016716:PC12 Cells; D051381:Rats; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D016019:Survival Analysis
D005419:Flavonoids; D044948:Flavonols; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D013267:Stilbenes; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C017875:fisetin; D000077185:Resveratrol