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Cited by 14Neuroinflammation and Neurodegeneration MechanismsParkinson's Disease Mechanisms and TreatmentsNuclear Receptors and Signaling

LRRK2 and WAVE2 regulate microglial‐transition through distinct morphological phenotypes to induce neurotoxicity in a novel two‐hit in vitro model of neurodegeneration

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Fenner, Barbara M., Fenner, Mark E., Prowse, Natalie, Hayley, Shawn P.·2022·Journal of Cellular Physiology
DOI 10.1002/jcp.30588
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Abstract

We report a novel in vitro classification system that tracks microglial activation state and their potential neurotoxicity. Mixed live‐cell imaging was used to characterize transition through distinct morphological phenotypes, production of reactive oxygen species (ROS), formation of reactive microglial aggregates, and subsequent cytokine production. Transwell cultures were used to determine microglial migration (control and lipopolysaccharide (LPS) treated) to glutamate pre‐stressed or healthy neurons. This two‐hit paradigm was developed to model the vast evidence that neurodegenerative conditions, like Parkinson's disease (PD), may stem from the collective impact of multiple environmental stressors. We found that healthy neurons were resistant to microglial‐mediated inflammation, whereas glutamate pre‐stressed neurons were highly susceptible and in fact, appeared to recruit microglia. The LPS treated microglia progressed through distinct morphological states and expressed high levels of ROS and formed large cellular aggregates. Recent evidence implicates leucine‐rich repeat kinase 2 (LRRK2) as an important player in the microglial inflammatory state, as well as in the genesis of PD. We found that inhibition of the LRRK2 signaling pathway using the kinase inhibitor cis‐2,6‐dimethyl‐4‐(6‐(5‐(1‐methylcyclopropoxy)‐1H‐indazol‐3‐yl)pyrimidin‐4‐yl)morpholine (MLi2) or inhibition of the actin regulatory protein, Wiskott‐Aldrich syndrome family Verprolin‐homologous Protein‐2 (WAVE2), stunted microglial activation and prevented neurotoxicity. Furthermore, inhibition of LRRK2 kinase activity reduced pro‐inflammatory chemokines including MIP‐2, CRG‐2, and RANTES. These data together support the notion that LRRK2 and WAVE2 are important mediators of cytokine production and cytoskeletal rearrangement necessary for microglial‐induced neurotoxicity. Furthermore, our model demonstrated unique microglial phenotypic changes that might be mechanistically important for better understanding neuron‐microglial crosstalk.

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  • An LRRK2 kinase inhibitor or an ARP2/3 inhibitor prevents microglial activation and neurotoxicity in vitro, suggesting the involvement of the LRRK2-WAVE2 pathway in microglia in PD pathogenesis.

    “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 [170]

    The Abstract reports that LRRK2 kinase inhibition or WAVE2 inhibition stunted microglial activation and prevented neurotoxicity in the in vitro model. Section 4.1.1 identifies the ARP2/3 inhibitor CK-869 as producing a less active microglial phenotype, and the paper links LRRK2 and WAVE2 to the model’s relevance for Parkinson’s disease. The claim overstates the activation result: the source reports reduced or delayed activation, not its complete prevention. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Fenner, B. M., Fenner, M. E., Prowse, N., & Hayley, S. P.
Affiliations
  • King's College - Pennsylvania (US)
  • Fenner Training and Consulting, LLC Kingston Pennsylvania USA
  • Carleton University (CA)
Corresponding author
Hayley, Shawn P.
ORCID
Venue
Journal of Cellular Physiology
Publisher
Wiley
Published
2021-09-20
Volume
237
Issue
1
Pages
1013-1032
ISSN
  • 0021-9541 (ISSN-L)
  • 1097-4652
DOI
10.1002/jcp.30588
OpenAlex
W3200180651
Cited by
14
References
5
Citations by year
2026: 3 · 2025: 4 · 2024: 1 · 2023: 2 · 2022: 4
FWCI
0.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Cellular Physiology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Canadian Institutes of Health Research (166068)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
LRRK2, WAVE2, microglial activation, microglial neurotoxicity, Parkinson's disease, two-hit model, glutamate excitotoxicity, lipopolysaccharide, reactive oxygen species, microglial migration, chemokine production, actin cytoskeleton, microglial morphology
MeSH terms
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Glutamates, Humans, Lipopolysaccharides, Parkinson Disease, Phenotype, Reactive Oxygen Species, Microglia, Chemokines, Neurotoxicity Syndromes, Wiskott-Aldrich Syndrome Protein Family

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