Nissley Daniel A, O'Brien Edward P
O'Brien Lab, Department of Chemistry, The Pennsylvania State University University Park, PA, USA.
Front Mol Neurosci. 2016 Jul 6;9:54. doi: 10.3389/fnmol.2016.00054. eCollection 2016.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG codon repeat region in the HTT gene's first exon that results in huntingtin protein aggregation and neuronal cell death. The development of therapeutic treatments for HD is hindered by the fact that while the etiology and symptoms of HD are understood, the molecular processes connecting this genotype to its phenotype remain unclear. Here, we propose the novel hypothesis that the perturbation of a co-translational process affects mutant huntingtin due to altered translation-elongation kinetics. These altered kinetics arise from the shift of a proline-induced translational pause site away from Htt's localization sequence due to the expansion of the CAG-repeat segment between the poly-proline and localization sequences. Motivation for this hypothesis comes from recent experiments in the field of protein biogenesis that illustrate the critical role that temporal coordination of co-translational processes plays in determining the function, localization, and fate of proteins in cells. We show that our hypothesis is consistent with various experimental observations concerning HD pathology, including the dependence of the age of symptom onset on CAG repeat number. Finally, we suggest three experiments to test our hypothesis.
亨廷顿舞蹈症（HD）是一种常染色体显性神经退行性疾病，由HTT基因第一个外显子中的CAG密码子重复区域扩增引起，导致亨廷顿蛋白聚集和神经元细胞死亡。尽管HD的病因和症状已为人所知，但将这种基因型与其表型联系起来的分子过程仍不清楚，这阻碍了HD治疗方法的开发。在此，我们提出一个新的假说，即共翻译过程的扰动会由于翻译延伸动力学的改变而影响突变型亨廷顿蛋白。这些改变的动力学源于脯氨酸诱导的翻译暂停位点因多脯氨酸序列和定位序列之间CAG重复片段的扩增而远离Htt的定位序列。这一假说的依据来自蛋白质生物合成领域最近的实验，这些实验表明共翻译过程的时间协调在决定细胞中蛋白质的功能、定位和命运方面起着关键作用。我们表明，我们的假说与关于HD病理学的各种实验观察结果一致，包括症状出现年龄对CAG重复数的依赖性。最后，我们提出了三个实验来检验我们的假说。
