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Human Molecular Genetics Advance Access published online on December 5, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi443
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received September 23, 2005
Accepted November 27, 2005

Article

Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity

Barbara L. Apostol 1, Katalin Illes 1, Judit Pallos 2, Laszlo Bodai 2, Jun Wu 3, Andrew Strand 4, Erik Schweitzer 3, James M. Olson 4, Aleksey Kazantsev 5, J. Lawrence Marsh 2, and Leslie Michels Thompson 1 *

1 Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697-4260
2 Developmental Biology Center and Department of Developmental and Cell Biology, University of California, Irvine, CA 92697-2300
3 Department of Neurobiology and Brain Research Institute, UCLA School of Medicine, Los Angeles, California 90095
4 Center for Aging and Neurodegeneration, Massachusetts General Hospital, Building 114-3300, 16th St., Charlestown, MA 02129
5 Division of Hematology/Oncology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98195


  Abstract

Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an expanded polyglutamine (polyQ) tract within the Huntingtin protein (Htt). Identifying pathways altered in response to the mutant protein is crucial to understanding the cellular processes impacted by the disease, as well as for the rational development of effective pharmacologic interventions. Here, expression profiling of a cellular HD model identifies genes implicating altered MAPK signaling. Targeted biochemical studies and pharmacologic 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 while inhibition of JNK was found to effectively suppress pathogenesis. These studies suggest that pharmacologic intervention in MAPK pathways, particularly at the level of ERK activation, may be an appropriate approach to HD therapy.


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