PDF(Pubmed)
Abstract：
Given their highly polarized morphology and functional singularity, neurons require precise spatial and temporal control of protein synthesis. Alterations in protein translation have been implicated in the development and progression of a wide range of neurological and neurodegenerative disorders, including Huntington\'s disease (HD). In this study we examined the architecture of polysomes in their native brain context in striatal tissue from the zQ175 knock-in mouse model of HD. We performed 3D electron tomography of high-pressure frozen and freeze-substituted striatal tissue from HD models and corresponding controls at different ages. Electron tomography results revealed progressive remodelling towards a more compacted polysomal architecture in the mouse model, an effect that coincided with the emergence and progression of HD related symptoms. The aberrant polysomal architecture is compatible with ribosome stalling phenomena. In fact, we also detected in the zQ175 model an increase in the striatal expression of the stalling relief factor EIF5A2 and an increase in the accumulation of eIF5A1, eIF5A2 and hypusinated eIF5A1, the active form of eIF5A1. Polysomal sedimentation gradients showed differences in the relative accumulation of 40S ribosomal subunits and in polysomal distribution in striatal samples of the zQ175 model. These findings indicate that changes in the architecture of the protein synthesis machinery may underlie translational alterations associated with HD, opening new avenues for understanding the progression of the disease.
摘要：
鉴于它们的高度极化形态和功能奇异性，神经元需要精确的空间和时间控制蛋白质的合成。蛋白质翻译的改变与广泛的神经和神经退行性疾病的发展和进展有关。包括亨廷顿病（HD）。在这项研究中，我们从zQ175敲入HD小鼠模型中检查了纹状体组织中天然大脑环境中多体的结构。我们对不同年龄的HD模型和相应对照进行了高压冷冻和冷冻替代纹状体组织的3D电子断层扫描。电子断层扫描结果显示，在小鼠模型中，逐渐向更紧凑的多体结构重构，与HD相关症状的出现和进展相吻合的效果。异常的多体结构与核糖体停滞现象相容。事实上,在zQ175模型中，我们还检测到停滞缓解因子EIF5A2的纹状体表达增加，eIF5A1，eIF5A2和eIF5A1的活性形式eIF5A1的积累增加。多体沉降梯度显示zQ175模型纹状体样品中40S核糖体亚基的相对积累和多体分布的差异。这些发现表明，蛋白质合成机制的结构变化可能是与HD相关的翻译改变的基础。为了解疾病的进展开辟了新的途径。
