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National Institute of Environmental Health Sciences

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Publication Detail

Title: LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia.

Authors: Kim, Judong; Pajarillo, Edward; Rizor, Asha; Son, Deok-Soo; Lee, Jayden; Aschner, Michael; Lee, Eunsook

Published In PLoS One, (2019)

Abstract: Long-term exposure to elevated levels of manganese (Mn) causes manganism, a neurodegenerative disorder with Parkinson's disease (PD)-like symptoms. Increasing evidence suggests that leucine-rich repeat kinase 2 (LRRK2), which is highly expressed in microglia and macrophages, contributes to the inflammation and neurotoxicity seen in autosomal dominant and sporadic PD. As gene-environment interactions have emerged as important modulators of PD-associated toxicity, LRRK2 may also mediate Mn-induced inflammation and pathogenesis. In this study, we investigated the role of LRRK2 in Mn-induced toxicity using human microglial cells (HMC3), LRRK2-wild-type (WT) and LRRK2-knockout (KO) RAW264.7 macrophage cells. Results showed that Mn activated LRRK2 kinase by phosphorylation of its serine residue at the 1292 position (S1292) as a marker of its kinase activity in macrophage and microglia, while inhibition with GSK2578215A (GSK) and MLi-2 abolished Mn-induced LRRK2 activation. LRRK2 deletion and its pharmacological inhibition attenuated Mn-induced apoptosis in macrophages and microglia, along with concomitant decreases in the pro-apoptotic Bcl-2-associated X (Bax) protein. LRRK2 deletion also attenuated Mn-induced production of reactive oxygen species (ROS) and the pro-inflammatory cytokine TNF-α. Mn-induced phosphorylation of mitogen-activated protein kinase (MAPK) p38 and ERK signaling proteins was significantly attenuated in LRRK2 KO cells and GSK-treated cells. Moreover, inhibition of MAPK p38 and ERK as well as LRRK2 attenuated Mn-induced oxidative stress and cytotoxicity. These findings suggest that LRRK2 kinase activity plays a critical role in Mn-induced toxicity via downstream activation of MAPK signaling in macrophage and microglia. Collectively, these results suggest that LRRK2 could be a potential molecular target for developing therapeutics to treat Mn-related neurodegenerative disorders.

PubMed ID: 30645642 Exiting the NIEHS site

MeSH Terms: Apoptosis*; Biomarkers/metabolism*; Cells, Cultured; Cytokines/metabolism; Humans; Inflammation/chemically induced; Inflammation/immunology; Inflammation/metabolism; Inflammation/pathology*; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism*; Manganese/adverse effects*; Microglia/drug effects; Microglia/immunology; Microglia/metabolism; Microglia/pathology*; Oxidative Stress*; Reactive Oxygen Species

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