Oxr1 Is Essential for Protection against Oxidative Stress-Induced Neurodegeneration

Abstract

Oxidative stress is a common etiological feature of neurological disorders, although the pathways that govern defence against reactive oxygen species (ROS) in neurodegeneration remain unclear. We have identified the role of oxidation resistance 1 (Oxr1) as a vital protein that controls the sensitivity of neuronal cells to oxidative stress; mice lacking Oxr1 display cerebellar neurodegeneration, and neurons are less susceptible to exogenous stress when the gene is over-expressed. A conserved short isoform of Oxr1 is also sufficient to confer this neuroprotective property both in vitro and in vivo. In addition, biochemical assays indicate that Oxr1 itself is susceptible to cysteine-mediated oxidation. Finally we show up-regulation of Oxr1 in both human and pre-symptomatic mouse models of amyotrophic lateral sclerosis, indicating that Oxr1 is potentially a novel neuroprotective factor in neurodegenerative disease.

Oxidation resistance 1 is a novel senolytic target

“…OXR1 is crucial for protecting cells against oxidative stress by regulating the expression of several enzymes that detoxify ROS (Jaramillo‐Gutierrez, Molina‐Cruz, Kumar & Barillas‐Mury, 2010; Oliver et al., 2011; Yang et al., 2015), and it may be particularly important as a senolytic target of PL because SCs are known to produce high levels of ROS but remain resistant to oxidative stress (Supporting Information Figure S2) (Chandrasekaran, Idelchik & Melendez, 2017; Davalli, Mitic, Caporali, Lauriola & D'Arca, 2016; Lee et al., 1999; Lu & Finkel, 2008). In addition, LMD‐3, homolog of OXR1 in Caenorhabditis elegans , has been shown to protect against oxidative stress and accelerated aging in the worm (Sanada et al., 2014).…”

“…OXR1 is an important antioxidant protein that protects cells from oxidative stress by regulating the expression of enzymes that detoxify ROS, such as glutathione peroxidase 2 (GTX2), heme oxygenase 1 (HO‐1), and catalase (CAT) (Jaramillo‐Gutierrez et al., 2010; Oliver et al., 2011; Yang et al., 2015). SCs are known to produce high levels of ROS, but they are highly resistant to oxidative stress (Chandrasekaran et al., 2017; Davalli et al., 2016; Lee et al., 1999; Lu & Finkel, 2008).…”

“…Among these possible senolytic targets of PL, we pursued OXR1 because it helps protect cells from oxidative stress by regulating several ROS‐detoxifying enzymes (Jaramillo‐Gutierrez et al., 2010; Oliver et al., 2011; Yang et al., 2015). Our studies showed that OXR1 is upregulated in both prematurely SCs induced by IR and replicative SCs in conjunction with the increased production of ROS and elevated expression of OXR1‐regulated ROS‐detoxifying enzymes such as GPX2, HO‐1, and CAT.…”

“…OXR1 is a cellular oxidative stress sensor that regulates the expression of a variety of antioxidant enzymes and modulates the cell cycle and apoptosis (Oliver et al., 2011; Yang et al., 2015). We found that OXR1 was upregulated in SCs induced by ionizing radiation (IR) or extensive replication.…”

Risk prediction of pulmonary tuberculosis using genetic and conventional risk factors in adult Korean population

“…Three genes, SRBD1 , CLIC5 , and KLHL36 , have been found to be involved in immune responses and reported to be associated with various phenotypes, such as glaucoma, neurological disorders, and carcinoma [23–25]. Dysfunction of the OXR1 gene resulted in increased oxidative stress associated with neurodegenerative disorders [26]. IGSF11 -specific activation has been reported to be correlated with HLA-A *0201-restricted cytotoxicy [27].…”