Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin
Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin
Date
2009-04-28
Authors
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.
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.
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Keywords
Huntingtin
Huntington's disease
Conventional kinesin
Kinesin-1
JNK
JNK3
Axonal transport
Neurodegeneration
Huntington's disease
Conventional kinesin
Kinesin-1
JNK
JNK3
Axonal transport
Neurodegeneration
Abstract
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.
Description
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.