HIF-1α and its downstream proteins in ALS model mice

Running Header: HIF-1α and its downstream proteins in ALS model mice HIF-1α and its downstream proteins in ALS model mice Sato, 2 INTRODUCTION Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease caused by the selective death of motor neurons. Approximately 5–10% of patients have a genetically inherited form known as familial ALS (FALS). Approximately 15–20% of FALS cases are associated with missense mutations or small deletions in the gene that encodes SOD1 mice that carry mutant SOD1 genes provided an animal model that has helped elucidate how mutations in the SOD1 gene cause motor neuron death (Gurney et al., 1994; Murakami et al., 2007). Although the underlying mechanism of ALS has not yet been fully clarified, several reports have implicated the involvement of oxidative stress in the selective death of motor neurons in both ALS patients and animal We previously showed blood flow-metabolism uncoupling in the affected spinal cords from the pre-symptomatic stage ALS model mice, suggesting relative spinal cord hypoxia (Miyazaki et al., 2011a). We also showed a selective lack of vascular endothelial growth factor (VEGF) induction in motor neurons (MNs) after hypoxic exposure in SOD1-Tg ALS model mice (Ilieva et al., 2003; Murakami et al., 2003). Other studies have suggested that the lack of VEGF induction is linked to the degeneration of HIF-1α and its downstream proteins in ALS model mice Sato, 3 al., 2003). Under hypoxic conditions, VEGF is activated by hypoxia inducible factor (HIF-1), which consists of a heterodimer of two basic helix-loop-helix PAS (Per-ARNT-Sim) proteins, HIF-1α and HIF-1β. HIF-1α accumulates in response to hypoxia, whereas HIF-1β is constitutively expressed. Thus, HIF1-α serves as an important mediator of the hypoxic response and upregulates important angiogenic factors, such as VEGF and VEGF receptor 1 (Sharp and Bernaudin, 2004). While HIF-1α expression is increased in the spinal cord of ALS model mice (Xu et al., 2011), the combination of HIF-1α and downstream proteins, such as heme oxygenase-1 (HO-1) and erythropoietin (EPO), as well as VEGF, have not been studied in ALS. In the present study, we examined temporal and spatial changes in HIF-1α, VEGF, HO-1, and EPO over the course of motor neuron degeneration in the spinal cord of ALS model mice. HIF-1α and its downstream proteins in ALS model mice Sato, 4 Nissl staining showed no change in the number of large motor neurons (MNs) in the lumbar spinal anterior horn at 10, 14 and …