The Huntington's disease mutation impairs Huntingtin's role in the transport of NF-κB from the synapse to the nucleus
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.
© 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].
Accepted Version - ddq358.pdf
Supplemental Material - ddq358supp.pdf