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The Huntington's disease mutation impairs Huntingtin's role in the transport of NF-κB from the synapse to the nucleus

Marcora, Edoardo and Kennedy, Mary B. (2010) The Huntington's disease mutation impairs Huntingtin's role in the transport of NF-κB from the synapse to the nucleus. Human Molecular Genetics, 19 (22). pp. 4373-4384. ISSN 0964-6906. PMCID PMC2957321. https://resolver.caltech.edu/CaltechAUTHORS:20101206-142344181

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Abstract

Expansion of a polyglutamine (polyQ) tract in the Huntingtin (Htt) protein causes Huntington's disease (HD), a fatal inherited neurodegenerative disorder. Loss of the normal function of Htt is thought to be an important pathogenetic component of HD. However, the function of wild-type Htt is not well defined. Htt is thought to be a multifunctional protein that plays distinct roles in several biological processes, including synaptic transmission, intracellular transport and neuronal transcription. Here, we show with biochemical and live cell imaging studies that wild-type Htt stimulates the transport of nuclear factor κ light-chain-enhancer of activated B cells (NF-κB) out of dendritic spines (where NF-κB is activated by excitatory synaptic input) and supports a high level of active NF-κB in neuronal nuclei (where NF-κB stimulates the transcription of target genes). We show that this novel function of Htt is impaired by the polyQ expansion and thus may contribute to the etiology of HD.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1093/hmg/ddq358DOIArticle
http://hmg.oxfordjournals.org/content/19/22/4373PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2957321/PubMed CentralArticle
ORCID:
AuthorORCID
Kennedy, Mary B.0000-0003-1369-0525
Additional Information:© The Author 2010. Published by Oxford University Press. Received June 8, 2010; Revised August 5, 2010; Accepted August 18, 2010. First published online: August 25, 2010. We are grateful to Pamela Bjorkman (Caltech, Pasadena, CA, USA) for the Htt exon 1 protein, Tinh Luong (Caltech) for the PSD-95 protein, Scott Zeitlin (University of Virginia, Charlottesville, VA, USA) for the Htt R1ag5 knock-out mice, Mike Levine (UCLA, Los Angeles, CA, USA) for the HD 140Q knock-in mice, Mollie Meffert (Johns Hopkins University, Baltimore, MD, USA) and members of the Kennedy laboratory for helpful discussions, and Leslie Schenker for technical assistance. Funding: This work was supported by the Hereditary Disease Foundation (New York, NY, USA); the Huntington’s Disease Society of America (New York, NY, USA); and the National Institutes of Health [NS028710].
Funders:
Funding AgencyGrant Number
Hereditary Disease FoundationUNSPECIFIED
Huntington’s Disease Society of AmericaUNSPECIFIED
NIHNS028710
Issue or Number:22
PubMed Central ID:PMC2957321
Record Number:CaltechAUTHORS:20101206-142344181
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20101206-142344181
Official Citation:Marcora, E. and M. B. Kennedy (2010). "The Huntington's disease mutation impairs Huntingtin's role in the transport of NF-κB from the synapse to the nucleus." Human Molecular Genetics 19(22): 4373-4384.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:21194
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:14 Dec 2010 00:15
Last Modified:03 Oct 2019 02:20

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