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

Barbara L. Apostol, Katalin Illes, Judit Pallos, Laszlo Bodai, Jun Wu, Andrew Strand, Erik S. Schweitzer, James M. Olson, Aleksey Kazantsev, J. Lawrence Marsh, Leslie Michels Thompson

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105 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)273-285
Number of pages13
JournalHuman molecular genetics
Volume15
Issue number2
DOIs
Publication statusPublished - Jan 15 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Apostol, B. L., Illes, K., Pallos, J., Bodai, L., Wu, J., Strand, A., Schweitzer, E. S., Olson, J. M., Kazantsev, A., Marsh, J. L., & Thompson, L. M. (2006). Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity. Human molecular genetics, 15(2), 273-285. https://doi.org/10.1093/hmg/ddi443