title: Mutant huntingtin interacts with {beta}-tubulin and disrupts vesicular transport and insulin secretion.
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.
authors.affiliation: Department of Experimental Medical Science, Lund University, Sweden.
authors.forename: Ruben
authors.initials: R
authors.lastname: Smith
authors.forename: Karl
authors.initials: K
authors.lastname: Bacos
authors.forename: Valentina
authors.initials: V
authors.lastname: Fedele
authors.forename: Denis
authors.initials: D
authors.lastname: Soulet
authors.forename: Helena A
authors.initials: HA
authors.lastname: Walz
authors.forename: Stefanie
authors.initials: S
authors.lastname: Obermüller
authors.forename: Anders
authors.initials: A
authors.lastname: Lindqvist
authors.forename: Maria
authors.initials: M
authors.lastname: Björkqvist
authors.forename: Pontus
authors.initials: P
authors.lastname: Klein
authors.forename: Patrik
authors.initials: P
authors.lastname: Onnerfjord
authors.forename: Patrik
authors.initials: P
authors.lastname: Brundin
authors.forename: Hindrik
authors.initials: H
authors.lastname: Mulder
authors.forename: Jia-Yi
authors.initials: JY
authors.lastname: Li
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D022161:Transport Vesicles / Q000235:genetics / Q000378:metabolism*; D014404:Tubulin / Q000235:genetics / Q000378:metabolism*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D007328:Insulin; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014404:Tubulin