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article, pubmed, cas, google, scholar, huntingtin, nature, palmitoylation, htt, disease, protein, research, hip, access, biol, cell, function, trafficking, neuronal, huntingtons, mutant, central, content, data, elhusseini, toxicity, mol, performed, cookies, huang, michael, hayden, polyglutamine, huntington, inclusion, hum, genet, supported, canada, british, columbia, privacy, mouse, neurons, pdf, open, model, neurosci, chem, mrh,

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n-methyl-d-aspartate receptor-mediated excitotoxicity nature portfolio permissions reprints privacy policy advertising neuronal development nature 431 nature social media palmitoylation-mediated synaptic regulation specific ubiquitin-conjugating enzyme research infrastructure unit alaa el-husseini canada research chair family research institute full-length mutant htt btn-bmcc palmitoylation assays springerlink instant access polyglutamine expansion-specific interaction lysosomal palmitoyl-protein thioesterase permissions huntingtin-interacting protein hip14 full-length htt palmitoylation rat brain neurons el-husseini health research medical research pharmacal research htt-transfected cos cells mutant huntingtin fragments increases neuronal toxicity synaptic strength regulated privacy [3h]palmitoylation assays personal data yac128 mouse model competing financial interests palmitoyl-protein thioesterase 2 palmitoyl-protein thioesterase full-length htt article yanai ampa receptor trafficking enhanced neuronal toxicity accelerates inclusion formation palmitoyl transferase involved wellcome/mrc building explore content subscription content function anat yanai characterized hip14 sirna

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         description:Post-translational modification by the lipid palmitate is crucial for the correct targeting and function of many proteins. Here we show that huntingtin (htt) is normally palmitoylated at cysteine 214, which is essential for its trafficking and function. The palmitoylation and distribution of htt are regulated by the palmitoyl transferase huntingtin interacting protein 14 (HIP14). Expansion of the polyglutamine tract of htt, which causes Huntington disease, results in reduced interaction between mutant htt and HIP14 and consequently in a marked reduction in palmitoylation. Mutation of the palmitoylation site of htt, making it palmitoylation resistant, accelerates inclusion formation and increases neuronal toxicity. Downregulation of HIP14 in mouse neurons expressing wild-type and mutant htt increases inclusion formation, whereas overexpression of HIP14 substantially reduces inclusions. These results suggest that the expansion of the polyglutamine tract in htt results in decreased palmitoylation, which contributes to the formation of inclusion bodies and enhanced neuronal toxicity.
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            address:
               name:Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Chicago, USA
               type:PostalAddress
            type:Organization
      name:Brinda Ravikumar
      affiliation:
            name:Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital
            address:
               name:Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:David C Rubinsztein
      affiliation:
            name:Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital
            address:
               name:Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Alaa El-Husseini
      affiliation:
            name:University of British Columbia
            address:
               name:Department of Psychiatry, University of British Columbia, Vancouver, Canada
               type:PostalAddress
            type:Organization
      email:[email protected]
      name:Michael R Hayden
      affiliation:
            name:Centre for Molecular Medicine and Therapeutics, University of British Columbia
            address:
               name:Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
               type:PostalAddress
            type:Organization
            name:Children and Family Research Institute, British Columbia Children's Hospital
            address:
               name:Children and Family Research Institute, British Columbia Children's Hospital, Vancouver, Canada
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
      name:Department of Psychiatry, University of British Columbia, Vancouver, Canada
      name:Department of Psychiatry, University of British Columbia, Vancouver, Canada
      name:Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
      name:Department of Psychiatry, University of British Columbia, Vancouver, Canada
      name:Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
      name:Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
      name:Department of Psychiatry, University of British Columbia, Vancouver, Canada
      name:Department of Psychiatry, University of British Columbia, Vancouver, Canada
      name:Department of Psychiatry, University of British Columbia, Vancouver, Canada
      name:Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Chicago, USA
      name:Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Chicago, USA
      name:Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Cambridge, UK
      name:Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Cambridge, UK
      name:Department of Psychiatry, University of British Columbia, Vancouver, Canada
      name:Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
      name:Children and Family Research Institute, British Columbia Children's Hospital, Vancouver, Canada
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