Altered expression of clock and clock-controlled genes in a hSOD1-linked amyotrophic lateral sclerosis mouse model.
Altered expression of clock and clock-controlled genes in a hSOD1-linked amyotrophic lateral sclerosis mouse model.
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hSOD 1连锁的肌萎缩侧索硬化小鼠模型中时钟和时钟控制基因的表达改变
DOI：
10.1096/fj.202000386rr
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Vargas MR
中科院分区：
文献类型：
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作者：
Killoy KM;Pehar M;Harlan BA;Vargas MR
哺乳动物的大多数生理过程都受到昼夜节律系统控制的每日振荡的影响。昼夜节律以时间依赖的方式协调代谢途径，昼夜节律的丧失与新陈代谢、氧化还原动态平衡和炎症的细胞和系统范围的变化有关。在这里，我们研究了突变的hSOD1连锁肌萎缩侧索硬化症(ALS)小鼠模型中时钟和时钟控制基因在多种组织(视交叉上核、脊髓、腓肠肌和肝脏)中的表达。我们确定了时钟基因、sirtuins(Sirt1、SIRT3和SIRT6)、代谢酶(PFKFB3、Cpt1和NAMPT)和氧化还原调节因子(Nrf2、G6PD、PGD)的相对表达和日常表达模式的组织特异性变化。此外，SOD1连锁和FUS RNA结合蛋白连锁的ALS患者诱导的多能干细胞转分化的星形胶质细胞也显示时钟基因的表达发生了变化。总体而言，我们的结果提高了hSOD1G93A小鼠视交叉上核和外周组织之间干扰的可能性，阻止了适当的外周时钟调节和同步。由于这些变化是在有症状的小鼠身上观察到的，目前尚不清楚这种调节失调是直接驱动还是退化过程的结果。然而，由于代谢和氧化还原动态平衡与昼夜节律密切相关，我们的数据表明时钟基因的表达改变可能有助于ALS的代谢和氧化还原损伤。由于昼夜节律不同步是可以挽救的，这些结果为潜在的疾病调整干预措施提供了基础。
Most physiological processes in mammals are subjected to daily oscillations that are governed by a circadian system. Circadian rhythm orchestrates metabolic pathways in a time-dependent manner and loss of circadian timekeeping has been associated with cellular and system-wide alterations in metabolism, redox homeostasis, and inflammation. Here, we investigated the expression of clock and clock-controlled genes in multiple tissues (suprachiasmatic nucleus, spinal cord, gastrocnemius muscle, and liver) from mutant hSOD1-linked amyotrophic lateral sclerosis (ALS) mouse models. We identified tissue-specific changes in the relative expression, as well as altered daily expression patterns, of clock genes, sirtuins (Sirt1, Sirt3 and Sirt6), metabolic enzymes (Pfkfb3, Cpt1 and Nampt) and redox regulators (Nrf2, G6pd, Pgd). In addition, astrocytes transdifferentiated from induced pluripotent stem cells from SOD1-linked and FUS RNA binding protein-linked ALS patients also displayed altered expression of clock genes. Overall, our results raise the possibility of disrupted cross-talk between the suprachiasmatic nucleus and peripheral tissues in hSOD1G93A mice, preventing proper peripheral clock regulation and synchronization. Since these changes were observed in symptomatic mice, it remains unclear whether this dysregulation directly drives or it is a consequence of the degenerative process. However, because metabolism and redox homeostasis are intimately entangled with circadian rhythms, our data suggest that altered expression of clock genes may contribute to metabolic and redox impairment in ALS. Since circadian dyssynchrony can be rescued, these results provide the groundwork for potential disease-modifying interventions.