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

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.