Peripheral inflammation mediates midbrain Lrrk2 kinase activity via Rab32 expression.

Mutations that increase leucine-rich repeat kinase 2 (LRRK2) activity confer significant risk for Parkinson's disease (PD), yet incomplete disease penetrance suggest additional factors are required to manifest disease. We recently identified RAB32 Ser71Arg as a Mendelian gene for PD. Here, we establish Rab32 as a key mediator linking peripheral inflammation to Lrrk2 activation. We show that Rab32 and Rab38 expression are modestly, but inversely, correlated with their homolog Rab29. In vivo , peripheral lipopolysaccharide (LPS)-induced inflammation selectively induced Rab32 expression in midbrain Iba1 + microglia but not dopaminergic neurons, where it localized to Lamp1 + lysosomal compartments and correlated with Lrrk2 kinase activity. LPS similarly induces Rab32 expression in human induced pluripotent stem cell-derived microglia, demonstrating a unified biological response to inflammation across species. Promoter analysis identified Tfe3, a master regulator of lysosomal biogenesis and autophagy, as a key driver of Rab32 expression induced Lrrk2 kinase activation. During inflammation, Tfe3 translocated to the nucleus of midbrain Iba1 + microglia to induce Rab32 expression and Lrrk2 kinase activity. Knockdown of Tfe3, but not Tfeb, mitigates these effects, establishing Rab32 as a physiological rheostat of Lrrk2 activity. This mechanistic pathway enables peripheral inflammation to modulate LRRK2 activity and highlights Rab32/Tfe3 as a therapeutic targeting for neuroprotection in PD.