Microglial NUS1 deficiency drives dopaminergic neurodegeneration through intercellular iron dysregulation in Parkinson's disease models.

Microglial NgBR (NUS1) deficiency in mice drives progressive PD-like motor deficits and dopaminergic neurodegeneration via the LCN2-SLC22A17 iron-transport axis.

• Why it matters: The mechanisms behind selective dopaminergic neuron loss in Parkinson’s disease remain unclear, despite NUS1 being linked to PD risk.
• What they did: In mice, NgBR-deficient microglia activated ER stress and PERK-ATF4-NUPR1 signaling, preferentially inducing LCN2-mediated iron efflux; microglia-derived iron-loaded Holo-LCN2 was taken up by SLC22A17 in dopaminergic neurons.
• The result: Pharmacological inhibition of the LCN2-SLC22A17 axis or ferroptosis alleviated dopaminergic neuron loss and PD-like symptoms caused by microglial NgBR deficiency in vitro and in vivo.