Department of Experimental Medical Science, Lund University, Sweden.
Hum Mol Genet. 2009 Oct 15;18(20):3942-54. doi: 10.1093/hmg/ddp336. Epub 2009 Jul 23.
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.
亨廷顿病是一种由 IT15 基因中的 CAG 扩展引起的严重进行性神经退行性疾病，该基因编码亨廷顿蛋白。该疾病主要影响纹状体和大脑皮层，也与糖尿病发病率增加有关。在这里，我们表明突变的亨廷顿蛋白通过直接干扰微管β-微管蛋白来破坏细胞内运输和胰岛素分泌。我们证明突变的亨廷顿蛋白在产生胰岛素的β细胞中损害葡萄糖刺激的胰岛素分泌，而不改变胰岛素的储存水平。使用 VSVG-YFP，我们表明突变的亨廷顿蛋白会延迟高尔基体后的运输。此外，我们证明胰岛素囊泡运输的速度降低。通过用突变和野生型亨廷顿蛋白进行免疫沉淀结合质谱分析，我们揭示了突变的亨廷顿蛋白和β-微管蛋白之间增强和异常的相互作用，暗示了细胞内运输受损的潜在机制。因此，我们的发现揭示了一种新的发病机制，突变的亨廷顿蛋白可能破坏β细胞中的激素胞吐作用，并可能损害任何表达致病性蛋白的细胞中的囊泡运输。
