Oxr1-KO Mouse

Oxr1, or Oxidation Resistance 1, is a highly conserved gene belonging to the TLDc domain-containing family. It is involved in multiple fundamental biological and cellular processes such as DNA damage response, antioxidant pathways, cell cycle, neuronal protection, and arginine methylation [3].

In Drosophila, knockdown of mtd (the fly homolog of OXR1) in adulthood inhibits dietary-restriction-mediated lifespan extension in female flies. Loss of mtd/OXR1 destabilizes the retromer, causing improper protein trafficking and endolysosomal defects, while overexpression of retromer genes or pharmacological restabilization can rescue lifespan and neurodegeneration in mtd-deficient flies [1]. In mice, lack of Oxr1 leads to cerebellar neurodegeneration, and over-expression makes neurons less susceptible to exogenous stress. A conserved short isoform of Oxr1 also confers neuroprotective property in vitro and in vivo [2]. In human patient-derived cells, a loss-of-function mutation in OXR1 impairs cell survival, proliferation, neural differentiation, and causes hypersensitivity to oxidative stress [3].

In conclusion, Oxr1 plays a crucial role in maintaining retromer function, protecting neurons from oxidative-stress-induced neurodegeneration, and is involved in neurodevelopment. The study of Oxr1 using gene knockout models in flies and mice, as well as patient-derived cell models, has provided insights into its function in aging-related processes and neurodegenerative diseases, offering potential therapeutic targets for these conditions.