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Hindrik Mulder

Hindrik Mulder

Principal investigator

Hindrik Mulder

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

Author

  • Ruben Smith
  • Karl Bacos
  • Valentina Fedele
  • Denis Soulet
  • Helena Jones
  • Stefanie Obermüller
  • Anders Lindqvist
  • Maria Björkqvist
  • Pontus Klein
  • Patrik Önnerfjord
  • Patrik Brundin
  • Hindrik Mulder
  • Jia-Yi Li

Summary, in English

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.

Department/s

  • Department of Experimental Medical Science
  • Insulin Signal Transduction
  • Islet cell physiology
  • Translational Neuroendocrinology
  • Rheumatology

Publishing year

2009

Language

English

Pages

3942-3954

Publication/Series

Human Molecular Genetics

Volume

18

Issue

20

Document type

Journal article

Publisher

Oxford University Press

Topic

  • Medical Genetics

Status

Published

Research group

  • Insulin Signal Transduction
  • Islet cell physiology
  • Translational Neuroendocrinology

ISBN/ISSN/Other

  • ISSN: 0964-6906