ARC Special Research Centre for the Molecular Genetics of Development and Discipline of Genetics, School of Molecular and Biomedical Sciences, The University of Adelaide, Adelaide, SA, Australia.
Hum Mol Genet. 2009 Dec 15;18(24):4830-42. doi: 10.1093/hmg/ddp455. Epub 2009 Sep 29.
Huntington's disease shares a common molecular basis with eight other neurodegenerative diseases, expansion of an existing polyglutamine tract. In each case, this repeat tract occurs within otherwise unrelated proteins. These proteins show widespread and overlapping patterns of expression in the brain and yet the diseases are distinguished by neurodegeneration in a specific subset of neurons that are most sensitive to the mutation. It has therefore been proposed that expansion of the polyglutamine region in these genes may result in perturbation of the normal function of the respective proteins, and that this perturbation in some way contributes to the neuronal specificity of these diseases. The normal functions of these proteins have therefore become a focus for investigation as potential pathogenic pathways. We have used synthetic antisense morpholinos to inhibit the translation of huntingtin mRNA during early zebrafish development and have previously reported the effects of huntingtin reduction on iron transport and homeostasis. Here we report an analysis of the effects of huntingtin loss-of-function on the developing nervous system, observing distinct defects in morphology of neuromasts, olfactory placode and branchial arches. The potential common origins of these defects were explored, revealing impaired formation of the anterior-most region of the neural plate as indicated by reduced pre-placodal and telencephalic gene expression with no effect on mid- or hindbrain formation. These investigations demonstrate a specific 'rate-limiting' role for huntingtin in formation of the telencephalon and the pre-placodal region, and differing levels of requirement for huntingtin function in specific nerve cell types.
亨廷顿病与其他八种神经退行性疾病具有共同的分子基础，即现有多聚谷氨酰胺区的扩展。在每种情况下，这种重复区都存在于其他不相关的蛋白质中。这些蛋白质在大脑中表现出广泛和重叠的表达模式，但这些疾病在特定的神经元亚群中表现出神经退行性变，这些神经元对突变最为敏感。因此，有人提出，这些基因中多聚谷氨酰胺区的扩展可能导致相应蛋白质正常功能的紊乱，而这种紊乱以某种方式导致了这些疾病的神经元特异性。因此，这些蛋白质的正常功能已成为研究的焦点，作为潜在的致病途径。我们使用合成反义形态发生素来抑制早期斑马鱼发育过程中的 httn mRNA 的翻译，并且之前已经报道了 httn 减少对铁运输和稳态的影响。在这里，我们报告了 huntingtin 功能丧失对发育中神经系统的影响的分析，观察到毛细胞、嗅基板和鳃弓的形态学明显缺陷。探讨了这些缺陷的潜在共同起源，显示出神经板最前部区域的形成受损，表现为前脑板和端脑基因表达减少，而对中脑或后脑的形成没有影响。这些研究表明，在端脑和前脑板区域的形成中，huntingtin 具有特定的“限速”作用，并且在特定的神经细胞类型中，对 huntingtin 功能的需求水平不同。
