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dc.contributor.authorLi, Tianxia
dc.contributor.authorNing, Bo
dc.contributor.authorKong, Lingbo
dc.contributor.authorDai, Bingling
dc.contributor.authorHe, Xiaofei
dc.contributor.authorThomas, Joseph M
dc.contributor.authorSawa, Akira
dc.contributor.authorRoss, Christopher A
dc.contributor.authorSmith, Wanli W
dc.date.accessioned2021-03-24T14:10:45Z
dc.date.available2021-03-24T14:10:45Z
dc.date.issued2021-02-23
dc.identifier.urihttp://hdl.handle.net/10713/15020
dc.description.abstractMutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant Parkinson's disease (PD) and contribute to sporadic PD. Common genetic variation in LRRK2 modifies susceptibility to immunological disorders including Crohn's disease and leprosy. Previous studies have reported that LRRK2 is expressed in B lymphocytes and macrophages, suggesting a role for LRRK2 in immunological functions. In this study, we characterized the LRRK2 protein expression and phosphorylation using human lymphoblasts. Lipopolysaccharide (LPS), a proinflammatory agent, induced the increase of LRRK2 expression and kinase activities in human lymphoblasts in a time-dependent manner. Moreover, LPS activated the Toll-like receptor (TLR) signaling pathway, increased TRAF6/LRRK2 interaction, and elevated the phosphorylation levels of MAPK (JNK1/2, p38, and ERK1/2) and IkBα. Treatment with LRRK2 inhibitor 68 reduced LPS-induced TRAF6/LRRK2 interaction and MAPK and IkBα phosphorylation, thereby reducing TNF-α secretion. These results indicate that LRRK2 is actively involved in proinflammatory responses in human lymphoblasts, and inhibition of GTP binding by 68 results in an anti-inflammation effect against proinflammatory stimuli. These findings not only provide novel insights into the mechanisms of LRRK2-linked immune and inflammatory responses in B-cell-like lymphoblasts, but also suggest that 68 may also have potential therapeutic value for LRRK2-linked immunological disorders.en_US
dc.description.urihttps://doi.org/10.3390/cells10020480en_US
dc.language.isoenen_US
dc.publisherMDPI AGen_US
dc.relation.ispartofCellsen_US
dc.subjectGTP binding inhibitoren_US
dc.subjectLPSen_US
dc.subjectLRRK2en_US
dc.subjectParkinson’s diseaseen_US
dc.subjectTNF-αen_US
dc.subjectlymphoblasten_US
dc.titleA LRRK2 GTP Binding Inhibitor, 68, Reduces LPS-Induced Signaling Events and TNF-α Release in Human Lymphoblastsen_US
dc.typeArticleen_US
dc.identifier.doi10.3390/cells10020480
dc.identifier.pmid33672296
dc.source.volume10
dc.source.issue2
dc.source.countrySwitzerland


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