Human Molecular Genetics Advance Access originally published online on December 5, 2005
Human Molecular Genetics 2006 15(2):273-285; doi:10.1093/hmg/ddi443
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Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity
1Department of Psychiatry and Human Behavior and 2Developmental Biology Center and Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA, 3Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90095, USA, 4Division of Hematology/Oncology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98195, USA, 5Department of Physiological Chemistry and Brain Research Institute, UCLA School of Medicine, Los Angeles, CA90095, USA and 6Center for Aging and Neurodegeneration, Massachusetts General Hospital, Building 114-3300, 16th Street, Charlestown, MA 02129, USA
* To whom correspondence should be addressed at: Gillespie 2121, University of California, Irvine, CA 92697-4260. Tel: +1 949 824 6756. Email: lmthompson{at}uci.edu
Received September 23, 2005; Accepted November 27, 2005
Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an expanded polyglutamine (polyQ) tract within the huntingtin protein (Htt). Identifying the pathways that are altered in response to the mutant protein is crucial for understanding the cellular processes impacted by the disease as well as for the rational development of effective pharmacological interventions. Here, expression profiling of a cellular HD model identifies genes that implicate altered mitogen-activated protein kinase (MAPK) signaling. Targeted biochemical studies and pharmacological modulation of these MAPK pathways suggest that mutant Htt affects signaling at upstream points such that both ERK and JNK are activated. Modulation of the ERK pathway suggests that this pathway is associated with cell survival, whereas inhibition of JNK was found to effectively suppress pathogenesis. These studies suggest that pharmacological intervention in MAPK pathways, particularly at the level of ERK activation, may be an appropriate approach to HD therapy.
These authors contributed equally to this work.
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