期刊
PLOS ONE
卷 7, 期 4, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0034693
关键词
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资金
- Korea Science and Engineering Foundation National Research Laboratory [2-2008025-0]
- Korean government (Ministry of Education, Science and Technology)
- Brain Research Center of the Twenty-First Century Frontier Research Program [M103KV010011-06K2201-01110]
- Ministry of Science and Technology, Republic of Korea
- Korea Science and Engineering Foundation through the Chronic Inflammatory Disease Research Center at Ajou University [R13-2003-019]
- National Research Foundation of Korea (NRF) [2009-00505, NRF-2008-521-C00220, NRF-2011-0012195]
- Inje FIRST (Inje University, Korea)
- National Research Foundation of Korea [2008-521-C00220, 2009-00505] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
LRRK2, a Parkinson's disease associated gene, is highly expressed in microglia in addition to neurons; however, its function in microglia has not been evaluated. Using Lrrk2 knockdown (Lrrk2-KD) murine microglia prepared by lentiviral-mediated transfer of Lrrk2-specific small inhibitory hairpin RNA (shRNA), we found that Lrrk2 deficiency attenuated lipopolysaccharide (LPS)-induced mRNA and/or protein expression of inducible nitric oxide synthase, TNF-alpha, IL-1 beta and IL-6. LPS-induced phosphorylation of p38 mitogen-activated protein kinase and stimulation of NF-kappa B-responsive luciferase reporter activity was also decreased in Lrrk2-KD cells. Interestingly, the decrease in NF-kappa B transcriptional activity measured by luciferase assays appeared to reflect increased binding of the inhibitory NF-kappa B homodimer, p50/p50, to DNA. In LPS-responsive HEK293T cells, overexpression of the human LRRK2 pathologic, kinase-active mutant G2019S increased basal and LPS-induced levels of phosphorylated p38 and JNK, whereas wild-type and other pathologic (R1441C and G2385R) or artificial kinase-dead (D1994A) LRRK2 mutants either enhanced or did not change basal and LPS-induced p38 and JNK phosphorylation levels. However, wild-type LRRK2 and all LRRK2 mutant variants equally enhanced NF-kappa B transcriptional activity. Taken together, these results suggest that LRRK2 is a positive regulator of inflammation in murine microglia, and LRRK2 mutations may alter the microenvironment of the brain to favor neuroinflammation.
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