Human Molecular Genetics Advance Access originally published online on July 23, 2009
Human Molecular Genetics 2009 18(20):3942-3954; doi:10.1093/hmg/ddp336
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Mutant huntingtin interacts with β-tubulin and disrupts vesicular transport and insulin secretion
1 Neuronal Survival Unit, BMC A10, Department of Experimental Medical Science, Lund University 221 84 Lund, Sweden, 2 Unit of Molecular Metabolism, Department of Clinical Sciences and 3 Unit of Islet Cell Physiology, CRC 91:11, 205 02 Malmö, Sweden, 4 Insulin Signal Transduction Group and 5 Connective Tissue Biology, BMC C12, 221 84 Lund, Sweden
* To whom correspondence should be addressed. Tel: +46 462220525; Fax: +46 462220531; Email: jia-yi.li{at}med.lu.se
Received June 1, 2009; Accepted July 20, 2009
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.