Microglial NUS1 deficiency drives dopaminergic neurodegeneration by activation of the LCN2/SLC22A17 axis-mediated iron transport

The mechanisms underlying selective loss of dopaminergic (DAergic) neurons in substantia nigra pars compacta in Parkinson’s disease (PD) remain unclear. The NUS1 gene, encoding NgBR, has recently been identified as a novel PD risk gene. Here, we show that NgBR is highly expressed in microglia, and microglia-specific NgBR deficiency drives progressive PD-like motor deficits and DAergic neurodegeneration via lipocalin-2 (LCN2)/SLC22A17 axis-mediated iron transport. NgBR deficiency in microglia triggers endoplasmic reticulum stress and PERK-ATF4-NUPR1 pathway to selectively upregulate LCN2-mediated iron efflux rather than cytokines. Strikingly, microglia-derived iron-loaded Holo-LCN2 but not iron-free Apo-LCN2 is internalized by SLC22A17, a receptor we identified as specifically highly expressed in DAergic neurons that induces iron overload/ferroptosis. Pharmacological inhibition of the LCN2/SLC22A17 axis or ferroptosis alleviate DAergic neuron loss and PD-like symptoms caused by microglial NgBR deficiency in vitro and in vivo. Our findings establish intercellular iron homeostasis imbalance as a selective pathological driver in PD and highlight the LCN2/SLC22A17 axis for specific therapeutic targeting.