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

Smith, Ruben LU ; Bacos, Karl LU ; Fedele, Valentina LU ; Soulet, Denis LU ; Jones, Helena LU ; Obermüller, Stefanie LU ; Lindqvist, Anders LU ; Björkqvist, Maria LU ; Klein, Pontus LU and Önnerfjord, Patrik LU , et al. (2009) In Human Molecular Genetics 18(20). p.3942-3954
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 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... (More)
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. (Less)
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Contribution to journal
publication status
published
subject
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Human Molecular Genetics
volume
18
issue
20
pages
3942 - 3954
publisher
Oxford University Press
external identifiers
  • wos:000270218300014
  • pmid:19628478
  • scopus:70349569018
ISSN
0964-6906
DOI
10.1093/hmg/ddp336
language
English
LU publication?
yes
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f2a5db26-a504-471d-bf00-964879dabeda (old id 1452862)
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http://www.ncbi.nlm.nih.gov/pubmed/19628478?dopt=Abstract
date added to LUP
2009-08-04 13:35:54
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2017-10-22 03:33:02
@article{f2a5db26-a504-471d-bf00-964879dabeda,
  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 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.},
  author       = {Smith, Ruben and Bacos, Karl and Fedele, Valentina and Soulet, Denis and Jones, Helena and Obermüller, Stefanie and Lindqvist, Anders and Björkqvist, Maria and Klein, Pontus and Önnerfjord, Patrik and Brundin, Patrik and Mulder, Hindrik and Li, Jia-Yi},
  issn         = {0964-6906},
  language     = {eng},
  number       = {20},
  pages        = {3942--3954},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Mutant huntingtin interacts with {beta}-tubulin and disrupts vesicular transport and insulin secretion.},
  url          = {http://dx.doi.org/10.1093/hmg/ddp336},
  volume       = {18},
  year         = {2009},
}