Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin

Gerardo A. Morfini, Yi Mei You, Sarah L. Pollema, Agnieszka Kaminska, Katherine Liu, Katsuji Yoshioka, Benny Björkblom, Eleanor T. Coffey, Carolina Bagnato, David Han, Chun Fang Huang, Gary Banker, Gustavo Pigino, Scott T. Brady

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174 Scopus citations

Abstract

Selected vulnerability of neurons in Huntington's disease suggests that alterations occur in a cellular process that is particularly critical for neuronal function. Supporting this idea, pathogenic Htt (polyQ-Htt) inhibits fast axonal transport (FAT) in various cellular and animal models of Huntington's disease (mouse and squid), but the molecular basis of this effect remains unknown. We found that polyQ-Htt inhibited FAT through a mechanism involving activation of axonal cJun N-terminal kinase (JNK). Accordingly, we observed increased activation of JNK in vivo in cellular and mouse models of Huntington's disease. Additional experiments indicated that the effects of polyQ-Htt on FAT were mediated by neuron-specific JNK3 and not by ubiquitously expressed JNK1, providing a molecular basis for neuron-specific pathology in Huntington's disease. Mass spectrometry identified a residue in the kinesin-1 motor domain that was phosphorylated by JNK3 and this modification reduced kinesin-1 binding to microtubules. These data identify JNK3 as a critical mediator of polyQ-Htt toxicity and provide a molecular basis for polyQ-Htt-induced inhibition of FAT.

Original languageEnglish (US)
Pages (from-to)864-871
Number of pages8
JournalNature Neuroscience
Volume12
Issue number7
DOIs
StatePublished - Jul 2009

ASJC Scopus subject areas

  • Neuroscience(all)

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    Morfini, G. A., You, Y. M., Pollema, S. L., Kaminska, A., Liu, K., Yoshioka, K., Björkblom, B., Coffey, E. T., Bagnato, C., Han, D., Huang, C. F., Banker, G., Pigino, G., & Brady, S. T. (2009). Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin. Nature Neuroscience, 12(7), 864-871. https://doi.org/10.1038/nn.2346