Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin
Morfini, Gerardo A.
Pollema, Sarah L.
Coffey, Eleanor T.
Pigino, Gustavo F.
Brady, Scott T.
MetadataShow full item record
KeywordHuntingtin; Huntington's disease; Conventional kinesin; Kinesin-1; JNK; JNK3; Axonal transport; Neurodegeneration
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.
Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of Nature America for personal use, not for redistribution. The definitive version was published in Nature Neuroscience 12 (2009): 864-871, doi:10.1038/nn.2346.
Showing items related by title, author, creator and subject.
The amino terminus of tau inhibits kinesin-dependent axonal transport: Implications for filament toxicity LaPointe, Nichole E.; Morfini, Gerardo A.; Pigino, Gustavo F.; Gaisina, Irina N.; Kozikowski, Alan P.; Binder, Lester I.; Brady, Scott T. (2008-04)The neuropathology of Alzheimer’s disease (AD) and other tauopathies is characterized by filamentous deposits of the microtubule-associated protein tau, but the relationship between tau polymerization and neurotoxicity ...
Dynamics of myosin, microtubules, and Kinesin-6 at the cortex during cytokinesis in Drosophila S2 cells Vale, Ronald D.; Spudich, James A.; Griffis, Eric R. (Rockefeller University Press, 2009-08)Signals from the mitotic spindle during anaphase specify the location of the actomyosin contractile ring during cytokinesis, but the detailed mechanism remains unresolved. Here, we have imaged the dynamics of green fluorescent ...
Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases Kanaan, Nicholas M.; Morfini, Gerardo A.; LaPointe, Nichole E.; Pigino, Gustavo F.; Patterson, Kristina R.; Song, Yuyu; Andreadis, Athena; Fu, Yifan; Brady, Scott T.; Binder, Lester I. (Society for Neuroscience, 2011-07-06)Aggregated filamentous forms of hyperphosphorylated tau (a microtubule-associated protein) represent pathological hallmarks of Alzheimer's disease (AD) and other tauopathies. While axonal transport dysfunction is thought ...