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PreprintPathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin( 2009-04-28) Morfini, Gerardo A. ; You, Yi-Mei ; Pollema, Sarah L. ; Kaminska, Agnieszka ; Liu, Katherine ; Yoshioka, Katsuji ; Bjorkblom, Benny ; Coffey, Eleanor T. ; Bagnato, Carolina ; Han, David ; Huang, Chun-Fang ; Banker, Gary ; Pigino, Gustavo F. ; Brady, Scott T.Selected vulnerability of neurons in Huntington’s disease (HD) suggests alterations in a cellular process particularly critical for neuronal function. Supporting this idea, pathogenic Htt (polyQ-Htt) inhibits fast axonal transport (FAT) in various cellular and animal HD models (mouse and squid), but the molecular basis of this effect remains unknown. Here we show that polyQ-Htt inhibits FAT through a mechanism involving activation of axonal JNK. Accordingly, increased activation of JNK was observed in vivo in cellular and animal HD models. Additional experiments indicate that polyQ-Htt effects on FAT are mediated by the neuron-specific JNK3, and not ubiquitously expressed JNK1, providing a molecular basis for neuron-specific pathology in HD. Mass spectrometry identified a residue in the kinesin-1 motor domain phosphorylated by JNK3, and this modification reduces kinesin-1 binding to microtubules. These data identify JNK3 as a critical mediator of polyQ-Htt toxicity and provides a molecular basis for polyQ-Htt-induced inhibition of FAT.