Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Sci Signal. 2024 Aug 6;17(848):eadl1030. doi: 10.1126/scisignal.adl1030.
Hexanucleotide repeat expansion in the gene is the most frequent inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansion results in multiple dipeptide repeat proteins, among which arginine-rich poly-GR proteins are highly toxic to neurons and decrease the rate of protein synthesis. We investigated whether the effect on protein synthesis contributes to neuronal dysfunction and degeneration. We found that the expression of poly-GR proteins inhibited global translation by perturbing translation elongation. In iPSC-differentiated neurons, the translation of transcripts with relatively slow elongation rates was further slowed, and stalled, by poly-GR. Elongation stalling increased ribosome collisions and induced a ribotoxic stress response (RSR) mediated by ZAKα that increased the phosphorylation of the kinase p38 and promoted cell death. Knockdown of ZAKα or pharmacological inhibition of p38 ameliorated poly-GR-induced toxicity and improved the survival of iPSC-derived neurons from patients with -ALS/FTD. Our findings suggest that targeting the RSR may be neuroprotective in patients with ALS/FTD caused by repeat expansion in .
基因中的六核苷酸重复扩展是肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）最常见的遗传原因。该扩展导致多种二肽重复蛋白，其中富含精氨酸的聚-GR 蛋白对神经元具有高度毒性，并降低蛋白质合成的速率。我们研究了这种对蛋白质合成的影响是否有助于神经元功能障碍和退化。我们发现，聚-GR 蛋白的表达通过扰乱翻译延伸来抑制整体翻译。在 iPSC 分化的神经元中，具有相对较慢延伸率的转录物的翻译进一步减慢，并因聚-GR 而停滞。延伸停滞增加了核糖体碰撞，并诱导由 ZAKα 介导的核糖体毒性应激反应 (RSR)，该反应增加激酶 p38 的磷酸化并促进细胞死亡。ZAKα 的敲低或 p38 的药理学抑制可改善聚-GR 诱导的毒性，并提高来自 -ALS/FTD 患者的 iPSC 衍生神经元的存活率。我们的发现表明，针对 RSR 可能对由 中的重复扩展引起的 ALS/FTD 患者具有神经保护作用。
