Kapur Mridu, Monaghan Caitlin E, Ackerman Susan L
Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, Section of Neurobiology, University of California, San Diego, La Jolla, CA 92093, USA.
Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, Section of Neurobiology, University of California, San Diego, La Jolla, CA 92093, USA.
Neuron. 2017 Nov 1;96(3):616-637. doi: 10.1016/j.neuron.2017.09.057.
Dynamic regulation of mRNA translation initiation and elongation is essential for the survival and function of neural cells. Global reductions in translation initiation resulting from mutations in the translational machinery or inappropriate activation of the integrated stress response may contribute to pathogenesis in a subset of neurodegenerative disorders. Aberrant proteins generated by non-canonical translation initiation may be a factor in the neuron death observed in the nucleotide repeat expansion diseases. Dysfunction of central components of the elongation machinery, such as the tRNAs and their associated enzymes, can cause translational infidelity and ribosome stalling, resulting in neurodegeneration. Taken together, dysregulation of mRNA translation is emerging as a unifying mechanism underlying the pathogenesis of many neurodegenerative disorders.
mRNA翻译起始和延伸的动态调节对于神经细胞的存活和功能至关重要。翻译机制中的突变或整合应激反应的不适当激活导致的翻译起始全局减少，可能在一部分神经退行性疾病的发病机制中起作用。非经典翻译起始产生的异常蛋白质可能是核苷酸重复扩增疾病中观察到的神经元死亡的一个因素。延伸机制的核心成分，如tRNA及其相关酶的功能障碍，可导致翻译错误和核糖体停滞，从而导致神经退行性变。综上所述，mRNA翻译失调正在成为许多神经退行性疾病发病机制的一个统一机制。
