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

Judong Kim, Edward Pajarillo, Asha Rizor, Deok Soo Son, Jayden Lee, Michael Aschner, Eunsook Lee

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere0210248
JournalPLoS One
Volume14
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

neuroglia
Microglia
Manganese
Leucine
leucine
manganese
phosphotransferases (kinases)
Phosphotransferases
apoptosis
inflammation
Apoptosis
Inflammation
Macrophages
mitogen-activated protein kinase
macrophages
Parkinson disease
Toxicity
Phosphorylation
neurodegenerative diseases
p38 Mitogen-Activated Protein Kinases

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia. / Kim, Judong; Pajarillo, Edward; Rizor, Asha; Son, Deok Soo; Lee, Jayden; Aschner, Michael; Lee, Eunsook.

In: PLoS One, Vol. 14, No. 1, e0210248, 01.01.2019.

Research output: Contribution to journalArticle

Kim, Judong ; Pajarillo, Edward ; Rizor, Asha ; Son, Deok Soo ; Lee, Jayden ; Aschner, Michael ; Lee, Eunsook. / LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia. In: PLoS One. 2019 ; Vol. 14, No. 1.
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