The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index.
Regulation of myeloid cell phagocytosis by LRRK2 via WAVE2 complex stabilization is altered in Parkinson’s disease
Open accessAbstract
Significance: Determining the role for LRRK2, the most common Parkinson’s disease (PD) gene in neurons has been a challenge for the field. Combining interaction data from an unbiased screen in flies and a conserved physical relationship, we show that LRRK2 binds and phosphorylates the actin remodeling protein WAVE2 specifically in myeloid cells. Furthermore, we demonstrate that this relationship is important for WAVE2 stability and the dynamics of the phagocytic response. Finally, we provide evidence that in both mammalian cocultures, flies, and a murine model of PD that LRRK2s action on WAVE2 may be important for neuronal survival. This work supports the role for LRRK2 in immune-signaling and the role for the immune system in the pathogenesis and progression of PD.
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“This complex regulates actin cytoskeleton organization and participates in cytokinesis, migration, endocytosis, and phagocytosis (14, 15).”
From Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Aβ amyloidosis (2021) · cites this paper as [14]
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“An LRRK2 kinase inhibitor or an ARP2/3 inhibitor prevents microglial activation and neurotoxicity in vitro169,170, suggesting the involvement of the LRRK2-WAVE2 pathway in microglia in PD pathogenesis.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [169]
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“LRRK2 binds and phosphorylates mouse WAVE2 at Thr470 (Thr471 in human WAVE2, Fig. 3b), stabilizing and preventing the proteasomal degradation of WAVE2, whereas LRRK2 does not interact with WAVE1169.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [169]
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“Macrophages or microglia isolated from PD patients or LRRK2-G2019S mice display increased phosphorylation at Thr470 on WAVE2 and enhanced phagocytic responses, but LRRK2 deletion causes the opposite effects.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [169]
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“WAVE2 levels are also reduced in primary microglia and bone marrow-derived macrophages from LRRK2 KO mice.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [169]
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“However, an increase in WAVE2 expression was observed in microglia and macrophages from LRRK2-G2019S knock-in mice169.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [169]
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“In addition, WAVE2 and its phosphorylation are involved in LRRK2-G2019S-induced dopaminergic neuronal death in macrophage and midbrain cocultures.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [169]
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“In BV2 microglia, LRRK2 knockdown reduces the level of WAVE2 but not the levels of WAVE1 and WAVE3.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [169]
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“Furthermore, WAVE2 knockdown in mice and Scar knockdown in Drosophila ameliorate LRRK2-G2019S-induced dopaminergic neuron loss169.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [169]
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“Recently, WAVE2 was found to be directly modulated by leucine rich repeat kinase 2 (LRRK2) in microglia, establishing a potentially pathogenic role in development of Parkinson disease [50].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [50]
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Citations
Cites
Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo
Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005) · Science · doi:10.1126/science.1110647 · Cited by 5,827
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Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease
the NIDDK IBD Genetics Consortium, Barrett, J. C., the Belgian-French IBD Consortium, the Wellcome Trust Case Control Consortium, Hansoul, S., Nicolae, D. L., Cho, J. H., Duerr, R. H., Rioux, J. D., Brant, S. R., et al. (2008) · Nature Genetics · doi:10.1038/ng.175 · Cited by 2,593
Self-citationAloisi, F. (2001) · Glia · doi:10.1002/glia.1106 · Cited by 1,310
Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases
Steger, M., Tonelli, F., Ito, G., Davies, P., Trost, M., Vetter, M., Wachter, S., Lorentzen, E., Duddy, G., Wilson, S., et al. (2016) · eLife · doi:10.7554/elife.12813 · Cited by 1,042
Phagocytosis and the actin cytoskeleton
May, R. C., & Machesky, L. M. (2001) · Journal of Cell Science · doi:10.1242/jcs.114.6.1061 · Cited by 715
Reciprocal Regulation between Resting Microglial Dynamics and Neuronal Activity In Vivo
Li, Y., Du, X.-F., Liu, C., Wen, Z., & Du, J. (2012) · Developmental Cell · doi:10.1016/j.devcel.2012.10.027 · Cited by 590
IRSp53 is an essential intermediate between Rac and WAVE in the regulation of membrane ruffling
Miki, H., Yamaguchi, H., Suetsugu, S., & Takenawa, T. (2000) · Nature · doi:10.1038/35047107 · Cited by 550
Structure and control of the actin regulatory WAVE complex
Chen, Z., Borek, D., Padrick, S. B., Gomez, T. S., Metlagel, Z., Ismail, A. M., Umetani, J., Billadeau, D. D., Otwinowski, Z., & Rosen, M. K. (2010) · Nature · doi:10.1038/nature09623 · Cited by 500
LRRK2 in Parkinson's disease: protein domains and functional insights
Mata, I. F., Wedemeyer, W. J., Farrer, M. J., Taylor, J. P., & Gallo, K. A. (2006) · Trends in Neurosciences · doi:10.1016/j.tins.2006.03.006 · Cited by 498
Research works printed but not linked: 1
- 10.1038/cdd.2012.166 · DOI
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Investigation of microglial diversity in a mouse model of Parkinson’s disease pathologyPreprint
Iovino, L., VanderZwaag, J., Kaur, G., Khakpour, P., Giusti, V., Chiavegato, A., Lopes, L. T., Greggio, E., Tremblay, M., & Civiero, L. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.11.23.567809 · Cited by 1
LRRK2 regulates synaptic function through modulation of actin cytoskeletal dynamicsPreprint
Tombesi, G., Kompella, S. N., Favetta, G., Chen, C., Ornaghi, M., Zhao, Y., Morosin, E., Sevegnani, M., Lama, A., Marte, A., et al. (2025) · eLife · doi:10.7554/elife.95987.2 · Cited by 1
Vastrad, B. M., Vastrad, C. M., & Kotturshetti, I. (2020) · medRxiv · doi:10.1101/2020.12.21.20248688
Elucidating the Role of LRRK2 Kinase Activity in the Innate Immune System
Lunn, M. O. (2019) · Carleton University's Institutional Repository (MacOdrum Library, Carleton University) · doi:10.22215/etd/2019-14737
LRRK2 regulates synaptic function through modulation of actin cytoskeletal dynamics
Tombesi, G., Kompella, S. N., Favetta, G., Chen, C., Ornaghi, M., Zhao, Y., Morosin, E., Sevegnani, M., Lama, A., Marte, A., et al. (2024) · eLife · doi:10.7554/elife.95987 · Cited by 1
Lu, Y., Wei, Z., Yu, X., Qin, L.-Z., Hu, L., Sun, S., & Yang, S.-L. (2025) · Microscopy and Microanalysis · doi:10.1093/mam/ozaf037
Berdasco, C., Cho, W.-H., Lee, J., Annu, A., Ledo, J. H., Jeong, Y. Y., Kim, Y.-S., An, S. S., Tanaka, Y., Ahn, J.-H., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.14.699391
LRRK2 regulates synaptic function through modulation of actin cytoskeletal dynamicsPreprint
Tombesi, G., Kompella, S. N., Favetta, G., Chen, C., Ornaghi, M., Zhao, Y., Morosin, E., Sevegnani, M., Lama, A., Marte, A., et al. (2026) · eLife · doi:10.7554/elife.95987.3
Metadata
- Authors
- Kim, K. S., Marcogliese, P. C., Yang, J., Callaghan, S. M., Resende, V., Abdel-Messih, E., Marras, C., Visanji, N. P., Huang, J., Schlossmacher, M. G., Trinkle-Mulcahy, L., Slack, R. S., Lang, A. E., Canadian Lrrk2 in Inflammation Team (CLINT), Park, D. S., Brown, E., Gibbings, D., Hayley, S., Park, D., Philpott, D. C., Rioux, J. D., Schlossmacher, M., & Schurr, E.
- Affiliations
- University of Ottawa (CA)
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada;
- University Health Network (CA)
- University of Toronto (CA)
- Brain and Mind Research Institute, University of Ottawa, Ottawa, ON K1H 8M5, Canada;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-05-14
- Volume
- 115
- Issue
- 22
- Pages
- E5164-E5173
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5984500
- OpenAlex
- W2803478714
- Cited by
- 111
- References
- 63
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 12 · 2023: 10 · 2022: 23 · 2021: 15 · 2020: 16 · 2019: 15 · 2018: 5
- FWCI
- 8.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Gouvernement du Canada | Canadian Institutes of Health Research (148402)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- LRRK2, Parkinson's disease, WAVE2, myeloid cells, phagocytosis, actin cytoskeleton remodeling, protein phosphorylation, protein stability, immune signaling, neuronal survival
- MeSH terms
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Animals, Cell Line, Drosophila, Humans, Parkinson Disease, Signal Transduction, Microglia, Myeloid Cells, Wiskott-Aldrich Syndrome Protein Family, Mice, Cytophagocytosis
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