Exploring the Diet Dependent Role of Oxidation Resistance 1 in regulating Retromer function

Abstract

Aging has been identified as a significant risk factor to the development of several diseases, such as neurodegeneration1. One of the most common age-related neurodegenerative diseases is Alzheimer’s Disease (AD)2, which causes cognitive decline. Current treatments for AD attempt to mitigate its symptoms or delay its onset3–5. One method that has shown promise not only for the treatment of AD, but also for increasing lifespan and healthspan overall is dietary restriction (DR)6, but the mechanisms by which DR mediates these effects remains unclear7,8. We have identified the human gene Oxidation Resistance 1 (OXR1) as an effector of DR for extended lifespan. We have found that D. melanogaster flies overexpressing OXR1 leads to a significant extension of both lifespan and healthspan on DR. In addition, it was shown that OXR1 confers neuroprotective benefits, but the mechanism by which it achieves these effects remains unclear. We have identified that OXR1 mediates this extension through its interactions with the retromer complex, a complex tied to AD due to its involvement in trafficking receptors that bind the pathological proteins of AD9–12. We observed that OXR1 co-localizes with retromer subunits, loss of OXR1 reduces retromer protein levels, and the loss of OXR1-retromer interaction with age is mitigated by DR. Supplementation with retromer therapeutics is able to restore both retromer protein levels and lifespan deficits caused by loss of OXR1. We also find knockdown or overexpression of each retromer subunit has different effects on lifespan. Lastly, we show loss of OXR1 is involved in numerous neurodegeneration pathways, correlates with AD diagnosis, and exacerbates AD pathology. These findings suggest that DR promotes prevention of neurodegeneration through OXR1-retromer interactions and OXR1 is a potential target that can be used to mitigate AD pathogenesis.