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Published November 15, 2010 | Accepted Version + Supplemental Material
Journal Article Open

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

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.

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].

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Accepted Version - ddq358.pdf

Supplemental Material - ddq358supp.pdf

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August 19, 2023
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