Fig. 7: Interferon-γ signaling synergizes with LRRK2 in human neurons and microglia.

IFN-γ response is conserved in DA neurons, and IFN-γ induces LRRK2 expression in DA neurons and microglia (a). The PD-associated mutation LRRK2 G2019S sensitizes DA neurons to IFN-γ by decreasing AKT phosphorylation (b) and suppressing NFAT nuclear shuttling (c) that, in turn, leads to defects in neurite outgrowth (d). LRRK2-dependent defects of NFAT translocation are linked to defects in calcium buffering capacity (e) and possibly to an increased complexity of the microtubule network (f). Defects in NFAT shuttling are also observed in LRRK2 G2019S microglia (g), which display a more activated phenotype upon stimulation. LRRK2 G2019S modulates microglia activation by interfering with the metabolic switch toward glycolysis that normally occurs upon mononuclear phagocyte activation (h) and impairing NF-κB p65 nuclear translocation upon stimulation with IFN-γ or LPS (i).