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

Nature Neuroscience volume 12, pages 864–871 (2009)Cite this article

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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.

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Figure 1: Endogenous Htt does not interact with molecular motors.
Figure 2: JNK inhibitors prevent polyQ-Htt-induced FAT inhibition.
Figure 3: PolyQ-Htt increases JNK activity in models of Huntington's disease.
Figure 4: The effects of polyQ-Htt on FAT are mediated by JNK3.
Figure 5: Active JNK3 mimics the effect of polyQ-Htt on FAT.
Figure 6: JNK3 phosphorylates kinesin-1 heavy chains at Ser176.
Figure 7: PolyQ-Htt expression inhibits kinesin-1 binding to microtubules.
Figure 8: A mutation mimicking Ser176 phosphorylation reduces the translocation efficiency of constitutively active kinesin-1 in cultured hippocampal neurons.

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  • 25 June 2009

    In the version of this article initially published, a critical word was missing. The sentence should read: "Conversely, antibodies to Htt immunoprecipitated Htt from both wild-type and homozygous HttQ109 knock-in mouse brain lysates, but kinesin-1, KLC, DIC and DHC could not be detected in Htt immunoprecipitates." The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We would like to thank M. MacDonald and M. DiFiglia for knock-in mice and huntingtin constructs, respectively, and B. Wang for excellent technical assistance. This work was supported by a 2007/2008 Marine Biological Laboratory summer fellowship to G.A.M., an Huntington's Disease Society of America grant to G.A.M., US National Institutes of Health grants MH066179 to G.B., and Amyotropic Lateral Sclerosis Association, Muscular Dystrophy Association and US National Institutes of Health (NS23868, NS23320, NS41170) grants to S.T.B.

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  1. Gerardo A Morfini and Yi-Mei You: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois, USA

    Gerardo A Morfini, Yi-Mei You, Sarah L Pollema, Agnieszka Kaminska, Gustavo Pigino & Scott T Brady

  2. Marine Biological Laboratory, Woods Hole, Massachusetts, USA

    Gerardo A Morfini, Sarah L Pollema, Katherine Liu, Gustavo Pigino & Scott T Brady

  3. Division of Molecular Cell Signaling, Cancer Research Institute, Kanazawa University, Japan

    Katsuji Yoshioka

  4. Turku Centre for Biotechnology, Åbo Akademi and Turku University, Turku, Finland

    Benny Björkblom & Eleanor T Coffey

  5. Center for Vascular Biology, University of Connecticut, Farmington, Connecticut, USA

    Carolina Bagnato & David Han

  6. The Jungers Center for Neurosciences Research, Oregon Health and Science University, Portland, Oregon, USA

    Chun-Fang Huang & Gary Banker

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Contributions

G.A.M. and S.T.B. carried out the transport and biochemistry experiments and wrote the manuscript. Y.-M.Y., S.L.P., A.K. and K.L. performed transport and biochemistry experiments. K.Y. provided and characterized recombinant JIP. B.B., E.T.C., C.B. and D.H. carried out the mass spectrometry studies. C.-F.H. and G.B. performed the GFP-kinesin experiments. G.P. performed axonal transport and biochemistry experiments. All of the authors reviewed and edited the manuscript.

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Correspondence to Gerardo A Morfini or Scott T Brady.

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Morfini, G., You, YM., Pollema, S. et al. Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin. Nat Neurosci 12, 864–871 (2009). https://doi.org/10.1038/nn.2346

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