Microglial NUS1 deficiency drives dopaminergic neurodegeneration through intercellular iron dysregulation in...

The selective loss of dopaminergic neurons in the substantia nigra pars compacta is a defining feature of Parkinson's disease (PD), yet its underlying mechanisms remain unclear. NUS1, which encodes neurite outgrowth inhibitor-B receptor (NgBR), was recently identified as a PD risk gene. Here we show that NgBR is highly expressed in microglia, where its deficiency drives progressive PD-like motor deficits and dopaminergic neurodegeneration via the LCN2-SLC22A17 iron-transport axis in mice. NgBR deficiency in mouse and human microglia triggers endoplasmic reticulum stress and PERK-ATF4-NUPR1 signaling, which preferentially induces LCN2-mediated iron efflux over cytokine release. Subsequently, microglia-derived iron-loaded Holo-LCN2, but not iron-free Apo-LCN2, is internalized by SLC22A17, a receptor highly expressed in dopaminergic neurons, leading to iron overload and ferroptosis. Pharmacological inhibition of LCN2-SLC22A17 axis or ferroptosis alleviated dopaminergic neuron loss and PD-like symptoms caused by microglial NgBR deficiency in vitro and in vivo. Our findings identify disrupted intercellular iron homeostasis as a pathological driver of PD and highlight the LCN2-SLC22A17 axis as a potential therapeutic target.