Role of LRRK2 in manganese-induced neuroinflammation and microglial autophagy

Journal Article · Thu Mar 15 04:00:00 EDT 2018 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2018.02.007· OSTI ID:23137263

Chen, Jiayan; Su, Peng; Luo, Wenjing; Chen, Jingyuan ^[1]

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1. Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, 710032 (China)

Highlights: • Manganese exposure up-regulated LRRK2 expression in substantia nigra. • LRRK2 expression was increased in BV2 microglia after Mn treatment. • Inhibiting LRRK2 expression inhibited Mn-induced microglia neuroinflammation. • LRRK2 regulated Mn-induced microglia autophagic disorders. Overexposure to manganese (Mn) leads to manganism and neurotoxicity induced by Mn is the focus of recent research. Microglia play a vital role in Mn-induced neurotoxicity, and our previous studies firstly showed that Mn could stimulate activation of microglia, leading to the neuroinflammation, and inhibition of microglial inflammation effectively attenuated Mn-induced death of dopamine neurons. However, the detailed mechanism of manganese-induced neuroinflammation is still unclear. Leucine rich repeat kinase 2 (LRRK2) is a key molecule in the pathogenesis of many neurodegenerative disorders. Recent studies have indicated that LRRK2, which is highly expressed in microglia, plays a specific role in microglia and autophagy process. In this paper, we try to find the effect of LRRK2 on Mn-triggered neuroinflammation and its possible mechanism in vivo and in vitro. By establishing a Mn exposure animal model, our studies found that Mn exposure could induce dopaminergic neurons damage and activate microglia. Activated microglia triggered neuroinflammation by releasing multiple inflammatory cytokines, and the expression of LRRK2 was upregulated in vivo and in vitro. We also found that Mn exposure induced autophagy dysfunction in vivo and in vitro. Next, we used LRRK2 siRNA and LRRK2-IN-1 to inhibit the expression of LRRK2, and found that inhibition of LRRK2 could not only decrease the expression of inflammatory cytokines, but also recover autophagic function of microglia. Our investigation not only reveals the role of LRRK2 in Mn-induced neuroinflammation but also sheds light on the prevention and protection of manganism.

• OSTI ID: 23137263
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 1 Vol. 498; ISSN 0006-291X; ISSN BBRCA9
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
DOPAMINE
INFLAMMATION
LEUCINE
LYMPHOKINES
NERVE CELLS
PHOSPHOTRANSFERASES