Adamla Frauke, Rollins Jarod, Newsom Matthew, Snow Santina, Schosserer Markus, Heissenberger Clemens, Horrocks Jordan, Rogers Aric N, Ignatova Zoya
Department of Chemistry and Biochemistry, University of Hamburg, Hamburg, Germany.
MDI Biological Laboratory, Davis Center for Regenerative Biology and Medicine, Salisbury Cove, ME, USA.
Cell Physiol Biochem. 2019;52(5):970-983. doi: 10.33594/000000067.
BACKGROUND/AIMS: Regulation of mRNA translation is central to protein homeostasis and is optimized for speed and accuracy. Spontaneous recoding events occur virtually at any codon but at very low frequency and are commonly assumed to increase as the cell ages.
Here, we leveraged the polyglutamine(polyQ)-frameshifting model of huntingtin exon 1 with CAG repeat length in the pathological range (Htt51Q), which undergoes enhanced non-programmed translational -1 frameshifting.
In body muscle cells of Caenorhabditis elegans, -1 frameshifting occured at the onset of expression of the zero-frame product, correlated with mRNA level of the non-frameshifted expression and formed aggregates correlated with reduced motility in C. elegans. Spontaneous frameshifting was modulated by IFG-1, the homologue of the nutrient-responsive eukaryotic initiation factor 4G (eIF4G), under normal growth conditions and NSUN-5, a conserved ribosomal RNA methyltransferase, under osmotic stress.
Our results suggest that frameshifting and aggregation occur at even early stages of development and, because of their intrinsic stability, may persist and accelerate the onset of age-related proteinopathies.
背景/目的：mRNA翻译的调控对于蛋白质稳态至关重要，并且在速度和准确性方面得到了优化。自发的重编码事件几乎可以在任何密码子处发生，但频率非常低，通常认为会随着细胞衰老而增加。
在这里，我们利用了亨廷顿蛋白外显子1的聚谷氨酰胺（polyQ）移码模型，其CAG重复长度处于病理范围内（Htt51Q），该模型会发生增强的非程序性翻译-1移码。
在秀丽隐杆线虫的体肌细胞中，-1移码发生在零框产物表达开始时，与非移码表达的mRNA水平相关，并形成与秀丽隐杆线虫运动能力降低相关的聚集体。在正常生长条件下，自发移码受到营养反应性真核起始因子4G（eIF4G）的同源物IFG-1的调节，在渗透应激下受到保守的核糖体RNA甲基转移酶NSUN-5的调节。
我们的结果表明，移码和聚集体形成甚至在发育的早期阶段就会发生，并且由于它们的内在稳定性，可能会持续存在并加速与年龄相关的蛋白质病的发生。
