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

Kim, Kwang Soo and Marcogliese, Paul C. and Yang, Jungwoo and Callaghan, Steve and Resende, Virginia and Abdel-Messih, Elizabeth and Marras, Connie and Visanji, Naomi P. and Huang, Jana and Schlossmacher, Michael G. and Tinkle-Mulcahy, Laura and Slack, Ruth S. and Lang, Anthony E. and Park, David S. (2018) Regulation of myeloid cell phagocytosis by LRRK2 via WAVE2 complex stabilization is altered in Parkinson’s disease. Proceedings of the National Academy of Sciences, 115 (22). ISSN 0027-84241091-6490

Abstract

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 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 pposite effect. LRRK2 binds and phosphorylates Wave2 at Thr470, stabilizing and preventing its
proteasomal degradation. Wave2 also mediates Lrrk2-G2019S-induced dopaminergic neuronal death in macrophage-midbrain co-cultures. Finally, in flies expressing Lrrk2-G2019S selectively in central phagocytes, we observed reduced lifespan, diminished locomotion, and increased dopaminergic cell loss as mediated by Scar/WAVE. Taken together, a LRRK2-WAVE2 pathway which regulates phagocytosis in mice and human leukocytes may define an important role for altered immune function in PD.

Item Type: Article
Date Deposited: 18 Sep 2018 00:45
Last Modified: 18 Sep 2018 00:45
URI: https://oak.novartis.com/id/eprint/34906

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