Mutations in Cu/Zn superoxide dismutase (SOD1) cause ~20% of familial ALS (FALS), which comprises 10% of total ALS cases. In mutant SOD1- (mtSOD1-) induced ALS, misfolded aggregates of SOD1 lead to activation of the unfolded protein response/integrated stress response (UPR/ISR). Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), a kinase that phosphorylates eukaryotic translation initiator factor 2α (p-eIF2α), coordinates the response by causing a global suppression of protein synthesis. Growth arrest and DNA damage 34 (GADD34) dephosphorylates p-eIF2α, allowing protein synthesis to return to normal. If the UPR/ISR is overwhelmed by the amount of misfolded protein, CCAAT/enhancer-binding homologous protein (CHOP) is activated leading to apoptosis. In the current study we investigated the effect of knocking down CHOP and GADD34 on disease of G93A and G85R mtSOD1 mice. Although a CHOP antisense oligonucleotide had no effect on survival, an intravenous injection of GADD34 shRNA encoded in adeno-associated virus 9 (AAV9) into neonatal G93A as well as neonatal G85R mtSOD1 mice led to a significantly increased survival. G85R mtSOD1 mice had a reduction in SOD1 aggregates/load, astrocytosis, and microgliosis. In contrast, there was no change in disease phenotype when GADD34 shRNA was delivered to older G93A mtSOD1 mice. Our current study shows that GADD34 shRNA is effective in ameliorating disease when administered to neonatal mtSOD1 mice. Targeting the UPR/ISR may be beneficial in mtSOD1-induced ALS as well as other neurodegenerative diseases in which misfolded proteins and ER stress have been implicated.

中文翻译：

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新生突变 SOD1 小鼠中 GADD34 的敲低可改善 ALS。


Cu/Zn 超氧化物歧化酶 (SOD1) 突变导致约 20% 的家族性 ALS (FALS)，占 ALS 病例总数的 10%。在突变型 SOD1- (mtSOD1-) 诱导的 ALS 中，SOD1 的错误折叠聚集体导致未折叠蛋白反应/整合应激反应 (UPR/ISR) 的激活。蛋白激酶 R (PKR) 样内质网激酶 (PERK) 是一种磷酸化真核翻译起始因子 2α (p-eIF2α) 的激酶，通过引起蛋白质合成的整体抑制来协调反应。生长停滞和 DNA 损伤 34 (GADD34) 使 p-eIF2α 去磷酸化，使蛋白质合成恢复正常。如果 UPR/ISR 被大量错误折叠蛋白淹没，CCAAT/增强子结合同源蛋白 (CHOP) 就会被激活，导致细胞凋亡。在当前的研究中，我们研究了敲低 CHOP 和 GADD34 对 G93A 和 G85R mtSOD1 小鼠疾病的影响。虽然 CHOP 反义寡核苷酸对存活率没有影响，但将腺相关病毒 9 (AAV9) 编码的 GADD34 shRNA 静脉注射到新生 G93A 和新生 G85R mtSOD1 小鼠中可显着提高存活率。 G85R mtSOD1 小鼠的 SOD1 聚集/负载、星形细胞增多和小胶质细胞增生减少。相比之下，当将 GADD34 shRNA 递送至老年 G93A mtSOD1 小鼠时，疾病表型没有变化。我们目前的研究表明，当给予新生 mtSOD1 小鼠时，GADD34 shRNA 可有效改善疾病。靶向 UPR/ISR 可能有益于 mtSOD1 诱导的 ALS 以及其他与错误折叠蛋白和 ER 应激有关的神经退行性疾病。