Regulation of myeloid cell phagocytosis by LRRK2 via WAVE2 complex stabilization is altered in Parkinson’s disease

Abstract

Leucine-rich repeat kinase 2 () has been implicated in both familial and sporadic Parkinson's disease (PD), yet its pathogenic role remains unclear. A previous screen in identified Scar/WAVE (Wiskott-Aldrich syndrome protein-family verproline) proteins as potential genetic interactors of Here, we provide evidence that LRRK2 modulates the phagocytic response of myeloid cells via specific modulation of the actin-cytoskeletal regulator, WAVE2. We demonstrate that macrophages and microglia from PD patients and mice display a WAVE2-mediated increase in phagocytic response, respectively. Lrrk2 loss results in the opposite effect. LRRK2 binds and phosphorylates Wave2 at Thr470, stabilizing and preventing its proteasomal degradation. Finally, we show that Wave2 also mediates Lrrk2G2019S-induced dopaminergic neuronal death in both macrophage-midbrain cocultures and in vivo. Taken together, a LRRK2-WAVE2 pathway, which modulates the phagocytic response in mice and human leukocytes, may define an important role for altered immune function in PD.

LRRK2 is recruited to phagosomes and co-recruits Rab8 and Rab10 in human pluripotent stem cell-derived macrophages

“…Parkinson's patients) has implicated LRRK2 in phagocytic uptake of beads or E.coli, through LRRK2 phosphorylating the actin-remodelling complex component, WAVE2 (Kim et al, 2018). It is not clear why our results diverge from this study, as hiPSCmacrophages express similar levels of WAVE2 to primary human monocytes and microglia (Haenseler et al, 2017a), but it may reflect technical differences (e.g.…”

Immune system responses in Parkinson's disease: Early and dynamic

“…For example, transgenic LRRK2 G2019S mice injected with LPS displayed altered peripheral immune responses (rather than alterations in microglia activation) that promoted dopaminergic neurodegeneration via soluble mediators (Kozina et al., ). LRRK2 has been associated with phagocytic activity of macrophages and microglia via phosphorylation of Scar [orthologous to human Wiskott‐Aldrich syndrome protein‐family verproline homologous 2 (Wave2)] that when compromised leads to dopaminergic cell death (Kim et al., ). Moreover, the LRRK2 (G2019S) mutation has been associated with expansion of myeloid cells with a bigger suppressive activity on CD4‐T cells that could not support a Th17 response (Park et al., ).…”

Environmental toxicant exposure and Parkinson’s disease: LRRK2 and inflammatory processes

“…Thus far, evidence has supported these findings in both cell culture and animal models of inflammation and PD [97]. Microglial and bone derived macrophages exposed to stimuli such as LPS and IFN-γ in vitro results in upregulation of LRRK2 protein and consequent microglial morphology and motility alterations [98][99][100]. A gene screen using drosophila discovered LRRK2 strongly interacts with SCAR a homologue of the mammalian Wiskott-Aldrich syndrome protein 2 (WAVE2) [101].…”

“…Moreover, the reduction in WAVE2 lung levels we observed might reflect general damage to tissue, or alternatively, variations in cell trafficking. WAVE2 is known to be crucial for the actin re-modelling in immune cells that are required for trafficking and processes such as phagocytosis [99,358]. Indeed, LRRK2 was reported to control phagocytic immune cell responses through the actin regulatory factor, WAVE2 [99], which also may be fundamental for basic inflammatory cell trafficking and inflammatory phenotype [358,359].…”

“…in regulating WAVE2-dependent inflammatory processes [99,358]. Specifically, WAVE2 would be expected to underlie phenotypic shifts in the activation state of inflammatory cells (particularly macrophages) and if this is regulated by LRRK2, then it's deficiency would limit inflammatory cell migration into organs.…”