title: 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.
authors.affiliation: Division of Biology, California Institute of Technology, 1200 E California Blvd., Pasadena, CA 91125, USA.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Marcora
authors.forename: Mary B
authors.initials: MB
authors.lastname: Kennedy
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055879:Gene Knock-In Techniques; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C499524:Htt protein, rat; D000071058:Huntingtin Protein; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine