Article abstract
Nature Neuroscience 12, 864 - 871 (2009)
Published online: 14 June 2009 | Corrected online: 25 June 2009 | doi:10.1038/nn.2346
Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin
Gerardo A Morfini1,2,7, Yi-Mei You1,7, Sarah L Pollema1,2, Agnieszka Kaminska1, Katherine Liu2, Katsuji Yoshioka3, Benny Björkblom4, Eleanor T Coffey4, Carolina Bagnato5, David Han5, Chun-Fang Huang6, Gary Banker6, Gustavo Pigino1,2 & Scott T Brady1,2
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.
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois, USA.
- Marine Biological Laboratory, Woods Hole, Massachusetts, USA.
- Division of Molecular Cell Signaling, Cancer Research Institute, Kanazawa University, Japan.
- Turku Centre for Biotechnology, Åbo Akademi and Turku University, Turku, Finland.
- Center for Vascular Biology, University of Connecticut, Farmington, Connecticut, USA.
- The Jungers Center for Neurosciences Research, Oregon Health and Science University, Portland, Oregon, USA.
- These authors contributed equally to this work.
Correspondence to: Gerardo A Morfini1,2,7 e-mail: gmorfini@uic.edu
Correspondence to: Scott T Brady1,2 e-mail: stbrady@uic.edu
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