Department of Neuroscience, Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Jefferson University, Philadelphia, PA, USA.
Department of Neuroscience, Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Jefferson University, Philadelphia, PA, USA
EMBO Mol Med. 2019 Feb;11(2). doi: 10.15252/emmm.201809423.
Nucleotide repeat expansions (NREs) are prevalent mutations in a multitude of neurodegenerative diseases. Repeat-associated non-AUG (RAN) translation of these repeat regions produces mono or dipeptides that contribute to the pathogenesis of these diseases. However, the mechanisms and drivers of RAN translation are not well understood. Here we analyzed whether different cellular stressors promote RAN translation of dipeptide repeats (DPRs) associated with the G4C2 hexanucleotide expansions in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that activating glutamate receptors or optogenetically increasing neuronal activity by repetitive trains of depolarization induced DPR formation in primary cortical neurons and patient derived spinal motor neurons. Increases in the integrated stress response (ISR) were concomitant with increased RAN translation of DPRs, both in neurons and different cell lines. Targeting phosphorylated-PERK and the phosphorylated-eif2α complex reduces DPR levels revealing a potential therapeutic strategy to attenuate DPR-dependent disease pathogenesis in NRE-linked diseases.
核苷酸重复扩展 (NREs) 是多种神经退行性疾病中普遍存在的突变。这些重复区域的重复相关非 AUG (RAN) 翻译产生单肽或二肽，导致这些疾病的发病机制。然而，RAN 翻译的机制和驱动因素尚不清楚。在这里，我们分析了不同的细胞应激是否会促进与 C9orf72 中 G4C2 六核苷酸扩展相关的二肽重复 (DPR) 的 RAN 翻译，C9orf72 是肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 的最常见遗传原因。我们发现，激活谷氨酸受体或通过重复去极化刺激来光遗传学地增加神经元活动，在原代皮质神经元和患者来源的脊髓运动神经元中诱导 DPR 形成。在神经元和不同细胞系中，整合应激反应 (ISR) 的增加伴随着 DPR 的 RAN 翻译增加。靶向磷酸化-PERK 和磷酸化-eif2α 复合物可降低 DPR 水平，这揭示了一种潜在的治疗策略，可减轻与 NRE 相关疾病中 DPR 依赖性疾病发病机制的影响。
