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Nature Neuroscience 12, 864–871 (1 July 2009) | doi:10.1038/nn.2346

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 Bj|[ouml]|rkblom , Eleanor T Coffey , Carolina Bagnato , David Han , Chun-Fang Huang , Gary Banker , Gustavo Pigino & Scott T Brady

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.