OXR1 maintains the retromer to delay brain aging under dietary restriction.
Kenneth A WilsonSudipta BarEric B DammerEnrique M CarreraBrian A HodgeTyler A U HilsabeckJoanna BonsGeorge W BrownridgeJennifer N BeckJacob RoseMelia Granath-PaneloChristopher S NelsonGrace QiAkos A GerencserJianfeng LanAlexandra AfenjarGeetanjali ChawlaRachel B BremPhilippe M CampeauHugo J BellenBirgit SchillingNicholas T SeyfriedLisa M EllerbyPankaj KapahiPublished in: Nature communications (2024)
Dietary restriction (DR) delays aging, but the mechanism remains unclear. We identified polymorphisms in mtd, the fly homolog of OXR1, which influenced lifespan and mtd expression in response to DR. Knockdown in adulthood inhibited DR-mediated lifespan extension in female flies. We found that mtd/OXR1 expression declines with age and it interacts with the retromer, which regulates trafficking of proteins and lipids. Loss of mtd/OXR1 destabilized the retromer, causing improper protein trafficking and endolysosomal defects. Overexpression of retromer genes or pharmacological restabilization with R55 rescued lifespan and neurodegeneration in mtd-deficient flies and endolysosomal defects in fibroblasts from patients with lethal loss-of-function of OXR1 variants. Multi-omic analyses in flies and humans showed that decreased Mtd/OXR1 is associated with aging and neurological diseases. mtd/OXR1 overexpression rescued age-related visual decline and tauopathy in a fly model. Hence, OXR1 plays a conserved role in preserving retromer function and is critical for neuronal health and longevity.
Keyphrases
- drosophila melanogaster
- poor prognosis
- binding protein
- transcription factor
- healthcare
- cell proliferation
- public health
- mental health
- editorial comment
- multiple sclerosis
- gene expression
- cerebral ischemia
- dna methylation
- white matter
- resting state
- genome wide
- brain injury
- functional connectivity
- health information
- genome wide identification