Mutant huntingtin interacts with {beta}-tubulin and disrupts vesicular transport and insulin secretion.
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.
Smith
Ruben
R
Department of Experimental Medical Science, Lund University, Sweden.
Bacos
Karl
K
Fedele
Valentina
V
Soulet
Denis
D
Walz
Helena A
HA
Obermüller
Stefanie
S
Lindqvist
Anders
A
Björkqvist
Maria
M
Klein
Pontus
P
Onnerfjord
Patrik
P
Brundin
Patrik
P
Mulder
Hindrik
H
Li
Jia-Yi
JY
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*
C086055:HTT protein, human; D000071058:Huntingtin Protein; D007328:Insulin; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014404:Tubulin