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

dc.contributor.author Morfini, Gerardo A.
dc.contributor.author You, Yi-Mei
dc.contributor.author Pollema, Sarah L.
dc.contributor.author Kaminska, Agnieszka
dc.contributor.author Liu, Katherine
dc.contributor.author Yoshioka, Katsuji
dc.contributor.author Bjorkblom, Benny
dc.contributor.author Coffey, Eleanor T.
dc.contributor.author Bagnato, Carolina
dc.contributor.author Han, David
dc.contributor.author Huang, Chun-Fang
dc.contributor.author Banker, Gary
dc.contributor.author Pigino, Gustavo F.
dc.contributor.author Brady, Scott T.
dc.date.accessioned 2009-12-16T19:57:30Z
dc.date.available 2009-12-16T19:57:30Z
dc.date.issued 2009-04-28
dc.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. en_US
dc.description.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. en_US
dc.description.sponsorship This work was supported by 2007/2008 MBL summer fellowship to GM; an HDSA grant to GM; NIH grants MH066179 to GB; and ALSA, Muscular Dystrophy Association, and NIH (NS23868, NS23320, NS41170) grants to STB. en_US
dc.format.mimetype application/pdf
dc.identifier.uri https://hdl.handle.net/1912/3096
dc.language.iso en_US en_US
dc.relation.uri https://doi.org/10.1038/nn.2346
dc.subject Huntingtin en_US
dc.subject Huntington's disease en_US
dc.subject Conventional kinesin en_US
dc.subject Kinesin-1 en_US
dc.subject JNK en_US
dc.subject JNK3 en_US
dc.subject Axonal transport en_US
dc.subject Neurodegeneration en_US
dc.title Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin en_US
dc.type Preprint en_US
dspace.entity.type Publication
relation.isAuthorOfPublication 1603077d-ae6e-4de0-8e61-a9d75812022b
relation.isAuthorOfPublication c2dd0b0e-d2c4-44ea-9aaf-bb0138665109
relation.isAuthorOfPublication ffcb0948-3a6a-4930-9a87-32d0016fd009
relation.isAuthorOfPublication 674a9597-9e85-4f13-a126-f159472291c3
relation.isAuthorOfPublication dbcfb587-ab3e-4181-9980-3ac00cc24f8e
relation.isAuthorOfPublication 5f8db4a8-8055-4815-9f49-589ff7c2bf7f
relation.isAuthorOfPublication 2f9b0518-b6e9-4243-9a89-bc9a80b503ae
relation.isAuthorOfPublication d7e6a5b2-f963-43f8-b176-ae0c207ff4a3
relation.isAuthorOfPublication 8f3ed63f-e39c-449f-81e2-914377999821
relation.isAuthorOfPublication b658f949-cc1b-4842-ab20-a879dcec80d9
relation.isAuthorOfPublication 456097ab-0d01-41cf-be9a-e041b7842f8f
relation.isAuthorOfPublication b7833178-5c24-4481-b94e-4f218e44c8fb
relation.isAuthorOfPublication d30495ae-bc39-4f8d-886a-8ef031c73e87
relation.isAuthorOfPublication 15e5161b-f250-41ed-b0ec-bac52ffa769e
relation.isAuthorOfPublication.latestForDiscovery 1603077d-ae6e-4de0-8e61-a9d75812022b
Files
Original bundle
Now showing 1 - 3 of 3
Thumbnail Image
Name:
MorfiniHtt Paper 280409f.pdf
Size:
257.8 KB
Format:
Adobe Portable Document Format
Description:
Author's draft
Thumbnail Image
Name:
figures.pdf
Size:
693.9 KB
Format:
Adobe Portable Document Format
Description:
Figures
Thumbnail Image
Name:
Supplemental figures.pdf
Size:
845.08 KB
Format:
Adobe Portable Document Format
Description:
Supplemental figures
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.97 KB
Format:
Item-specific license agreed upon to submission
Description: