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  • Smith, RubenLund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine (author)

Mutant huntingtin interacts with {beta}-tubulin and disrupts vesicular transport and insulin secretion.

  • Article/chapterEnglish2009

Publisher, publication year, extent ...

  • 2009-07-23
  • Oxford University Press (OUP),2009

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  • LIBRIS-ID:oai:lup.lub.lu.se:f2a5db26-a504-471d-bf00-964879dabeda
  • https://lup.lub.lu.se/record/1452862URI
  • https://doi.org/10.1093/hmg/ddp336DOI

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  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • Huntington's disease is a severe progressive neurodegenerative disorder caused by a CAG-expansion in the IT15 gene, which encodes huntingtin. The disease primarily affects the neostriatum and cerebral cortex and also associates with increased incidence of diabetes. Here, we show that mutant huntingtin disrupts intracellular transport and insulin secretion by direct interference with microtubular beta-tubulin. We demonstrate that mutant huntingtin impairs glucose-stimulated insulin secretion in insulin-producing beta-cells, without altering stored levels of insulin. Using VSVG-YFP, we show that mutant huntingtin retards post-Golgi transport. Moreover, we demonstrate that the speed of insulin vesicle trafficking is reduced. Using immunoprecipitation of mutant and wild-type huntingtin in combination with mass spectrometry, we reveal an enhanced and aberrant interaction between mutant huntingtin and beta-tubulin, implying the underlying mechanism of impaired intracellular transport. Thus, our findings have revealed a novel pathogenetic process by which mutant huntingtin may disrupt hormone exocytosis from beta-cells and possibly impair vesicular transport in any cell that expresses the pathogenic protein.

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  • Bacos, KarlLund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine(Swepub:lu)medk-kb0 (author)
  • Fedele, ValentinaLund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine(Swepub:lu)med-vtf (author)
  • Soulet, DenisLund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine(Swepub:lu)med-des (author)
  • Jones, HelenaLund University,Lunds universitet,Signaltransduktionsforskning,Forskargrupper vid Lunds universitet,Insulin Signal Transduction,Lund University Research Groups(Swepub:lu)medk-hwa (author)
  • Obermüller, StefanieLund University,Lunds universitet,Islet cell physiology,Forskargrupper vid Lunds universitet,Lund University Research Groups(Swepub:lu)mphy-sob (author)
  • Lindqvist, AndersLund University,Lunds universitet,Islet cell physiology,Forskargrupper vid Lunds universitet,Lund University Research Groups(Swepub:lu)mphy-ali (author)
  • Björkqvist, MariaLund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Translationell neuroendokrinologi,Forskargrupper vid Lunds universitet,Department of Experimental Medical Science,Faculty of Medicine,Translational Neuroendocrinology,Lund University Research Groups(Swepub:lu)farm-mbj (author)
  • Klein, PontusLund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine(Swepub:lu)med-pke (author)
  • Önnerfjord, PatrikLund University,Lunds universitet,Reumatologi och molekylär skelettbiologi,Sektion III,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Rheumatology,Section III,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)akem-pon (author)
  • Brundin, PatrikLund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine(Swepub:lu)mphy-pbr (author)
  • Mulder, HindrikLund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine(Swepub:lu)medk-hmu (author)
  • Li, Jia-YiLund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine(Swepub:lu)mphy-jli (author)
  • Institutionen för experimentell medicinsk vetenskapMedicinska fakulteten (creator_code:org_t)

Related titles

  • In:Human Molecular Genetics: Oxford University Press (OUP)18:20, s. 3942-39540964-69061460-2083

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