Mutant huntingtin interacts with β-tubulin and disrupts vesicular transport and insulin secretion

Ruben Smith, Karl Bacos, Valentina Fedele, Denis Soulet, Helena A. Walz, Stefanie Obermüller, Anders Lindqvist, Maria Björkqvist, Pontus Klein, Patrik Önnerfjord, Patrik Brundin, Hindrik Mulder, Jia Yi Li

Research output: Contribution to journalArticle

Abstract

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 β-tubulin. We demonstrate that mutant huntingtin impairs glucose-stimulated insulin secretion in insulin-producing β-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 β-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 β-cells and possibly impair vesicular transport in any cell that expresses the pathogenic protein.

Original languageEnglish
Pages (from-to)3942-3954
Number of pages13
JournalHuman Molecular Genetics
Volume18
Issue number20
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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    Smith, R., Bacos, K., Fedele, V., Soulet, D., Walz, H. A., Obermüller, S., Lindqvist, A., Björkqvist, M., Klein, P., Önnerfjord, P., Brundin, P., Mulder, H., & Li, J. Y. (2009). Mutant huntingtin interacts with β-tubulin and disrupts vesicular transport and insulin secretion. Human Molecular Genetics, 18(20), 3942-3954. https://doi.org/10.1093/hmg/ddp336