Altered expression of clock and clock-controlled genes in a hSOD1-linked amyotrophic lateral sclerosis mouse model.

Abstract

Most physiological processes in mammals are subjected to daily oscillations that are governed by a circadian system. The 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, and 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.