{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T14:19:15Z","timestamp":1772720355460,"version":"3.50.1"},"reference-count":55,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T00:00:00Z","timestamp":1632096000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We report a novel in vitro classification system that tracks microglial activation state and their potential neurotoxicity. Mixed live\u2010cell 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\u2010stressed or healthy neurons. This two\u2010hit 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\u2010mediated inflammation, whereas glutamate pre\u2010stressed 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\u00a0and formed large cellular aggregates. Recent evidence implicates leucine\u2010rich 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\u20102,6\u2010dimethyl\u20104\u2010(6\u2010(5\u2010(1\u2010methylcyclopropoxy)\u20101H\u2010indazol\u20103\u2010yl)pyrimidin\u20104\u2010yl)morpholine (MLi2) or inhibition of the actin regulatory protein, Wiskott\u2010Aldrich syndrome family Verprolin\u2010homologous Protein\u20102 (WAVE2), stunted microglial activation and prevented neurotoxicity. Furthermore, inhibition of LRRK2 kinase activity reduced pro\u2010inflammatory chemokines including MIP\u20102, CRG\u20102, and RANTES. These data together support the notion that LRRK2 and WAVE2 are important mediators of cytokine production and cytoskeletal rearrangement necessary for microglial\u2010induced neurotoxicity. Furthermore, our model demonstrated unique microglial phenotypic changes that might be mechanistically important for better understanding neuron\u2010microglial crosstalk.<\/jats:p>","DOI":"10.1002\/jcp.30588","type":"journal-article","created":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T18:44:28Z","timestamp":1632163468000},"page":"1013-1032","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["LRRK2 and WAVE2 regulate microglial\u2010transition through distinct morphological phenotypes to induce neurotoxicity in a novel two\u2010hit in vitro model of neurodegeneration"],"prefix":"10.1002","volume":"237","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5535-3792","authenticated-orcid":false,"given":"Barbara M.","family":"Fenner","sequence":"first","affiliation":[{"name":"Department of Biology King's College  Wilkes\u2010Barre Pennsylvania 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