Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 22, Pages E5164-E5173Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1718946115
Keywords
Parkinson's disease; LRRK2; WAVE2; WASF2; microglia
Categories
Funding
- Michael J. Fox Foundation for Parkinson Research
- Canadian Institutes of Health Research [148402]
- Weston Brain Institute, Parkinson Society Canada
- Parkinson Research Consortium
- Network of Centers of Excellence in Neurodegeneration (JPND)
- Ontario Brain Institute
- Heart and Stroke Foundation of Ontario
- Neuroscience Brain Canada/Krembil Foundation
- Parkinson Society Canada
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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.
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