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

2009; Nature Portfolio; Volume: 12; Issue: 7 Linguagem: Inglês

10.1038/nn.2346

1546-1726

Gerardo Morfini, Yimei You, Sarah L. Pollema, Agnieszka Kamińska, Katherine Liu, Katsuji Yoshioka, Benny Björkblom, Eleanor T. Coffey, Carolina Bagnato, David K. Han, Chun-Fang Huang, Gary Banker, Gustavo Pigino, Scott T. Brady,

Neurological disorders and treatments

PolyQ-Htt inhibits fast axonal transport in cellular and animal Huntington's disease models. Here, the authors show that this effect is a result of the activation of JNK3. PolyQ-Htt–activated JNK3 reduces kinesin-1 binding to microtubules. 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.