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Proc Natl Acad Sci U S A. 2018 May 29;115(22):E5164-E5173. doi: 10.1073/pnas.1718946115. Epub 2018 May 14.

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

Author information

1
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
2
Brain and Mind Research Institute, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
3
Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 0M5, Canada.
4
Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, Toronto, ON M5T 2S8, Canada.
5
Edmond J. Safra Program in Parkinson's Disease, University of Toronto, Toronto, ON M5S 1A8, Canada.
6
Division of Neuroscience, Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON K1H 8M5, Canada.
7
Division of Neurology, The Ottawa Hospital, Ottawa, ON K1H 8M5, Canada.
8
Division of Neurology, Department of Medicine, Toronto Western Hospital, University Health Network, Toronto, ON M5T 2S8, Canada.
9
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; dpark@uottawa.ca.

Abstract

Leucine-rich repeat kinase 2 (LRRK2) has been implicated in both familial and sporadic Parkinson's disease (PD), yet its pathogenic role remains unclear. A previous screen in Drosophila identified Scar/WAVE (Wiskott-Aldrich syndrome protein-family verproline) proteins as potential genetic interactors of LRRK2 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 LRRK2-G2019S 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 Lrrk2-G2019S-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.

KEYWORDS:

LRRK2; Parkinson’s disease; WASF2; WAVE2; microglia

PMID:
29760073
PMCID:
PMC5984500
DOI:
10.1073/pnas.1718946115
[Indexed for MEDLINE]
Free PMC Article

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