An LRRK2 variant blocks NCOA4 trafficking upon iron overload, leading to ferroptotic death.

Altered iron homeostasis has long been implicated in Parkinson's disease (PD), although the mechanisms have not been clear. Given the critical role of PD-related activating variants in leucine-rich repeat protein kinase 2 (LRRK2) within membrane trafficking pathways, we examined the impact of the homozygous variant LRRK2G2019S on iron homeostasis within the RAW264.7 mouse macrophage cell line with high iron capacity. Proteomics analysis revealed a dysregulation of iron-related proteins in steady state, with highly elevated levels of ferritin light chain (FTL1) and a reduction of ferritin heavy chain (FTH1). LRRK2G2019S mutant cells showed efficient ferritinophagy upon iron chelation, but upon iron overload, there was a near-complete block in the degradation of the ferritinophagy adaptor NCOA4. These conditions led to an accumulation of phosphorylated Rab8 (RAB8A) at the plasma membrane, which is selectively inhibited by LRRK type II kinase inhibitors. Iron overload then led to increased oxidative stress and ferroptotic cell death. These data implicate LRRK2 as a key regulator of iron homeostasis and point to the need for an increased focus on the mechanisms of iron dysregulation in PD.