LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia.
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...
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Public Library of Science (PLoS)
2019-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0210248&type=printable |
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| author | Judong Kim Edward Pajarillo Asha Rizor Deok-Soo Son Jayden Lee Michael Aschner Eunsook Lee |
| author_facet | Judong Kim Edward Pajarillo Asha Rizor Deok-Soo Son Jayden Lee Michael Aschner Eunsook Lee |
| author_sort | Judong Kim |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a6b4c622b6b94dc68ee242edd809f296 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-a6b4c622b6b94dc68ee242edd809f2962025-08-20T01:55:28ZengPublic Library of Science (PLoS)PLoS ONE1932-62032019-01-01141e021024810.1371/journal.pone.0210248LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia.Judong KimEdward PajarilloAsha RizorDeok-Soo SonJayden LeeMichael AschnerEunsook LeeLong-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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0210248&type=printable |
| spellingShingle | Judong Kim Edward Pajarillo Asha Rizor Deok-Soo Son Jayden Lee Michael Aschner Eunsook Lee LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia. PLoS ONE |
| title | LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia. |
| title_full | LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia. |
| title_fullStr | LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia. |
| title_full_unstemmed | LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia. |
| title_short | LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia. |
| title_sort | lrrk2 kinase plays a critical role in manganese induced inflammation and apoptosis in microglia |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0210248&type=printable |
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