title: Phosphorylation of p53 by LRRK2 induces microglial tumor necrosis factor α-mediated neurotoxicity.
abstract: Leucine-rich repeat kinase (LRRK2), a major causal gene of Parkinson's disease (PD), functions as a kinase. The most prevalent mutation of LRRK2 is G2019S. It exhibits increased kinase activity compared to the wildtype LRRK2. Previous studies have shown that LRRK2 can phosphorylate p53 at T304 and T377 of threonine-X-arginine (TXR) motif in neurons. Reduction of LRRK2 expression or inhibition of LRRK2 kinase activity has been shown to be able to alleviate LPS-induced neuroinflammation in microglia cells. In this study, we found that LRRK2 could also phosphorylate p53 in microglia model BV2 cells. Transfection of BV2 with phosphomimetic p53 T304/377D significantly increased the secretion of pro-inflammatory cytokine TNFα compared to BV2 transfected with p53 wild type after LPS treatment. In addition, conditioned media from these transfected cells increased the death of dopaminergic neuronal SN4741 cells. Moreover, such neurotoxic effect was rescued by co-treatment with the conditioned media and etanercept, a TNFα blocking antibody. Furthermore, TNFα secretion was significantly increased in primary microglia derived from G2019S transgenic mice treated with LPS compared to that in cells derived from their littermates. These results suggest that LRRK2 kinase activity in microglia can contribute to neuroinflammation in PD via phosphorylating p53 at T304 and T377 site.
authors.affiliation: InAm Neuroscience Research Center, Sanbon Medical Center, Collage of Medicine, Wonkwang University, 321 Sanbon-ro, Gunposhi, Gyeonggido, Republic of Korea. Electronic address: ethan2887@gmail.com.
authors.forename: Dong Hwan
authors.initials: DH
authors.lastname: Ho
authors.affiliation: InAm Neuroscience Research Center, Sanbon Medical Center, Collage of Medicine, Wonkwang University, 321 Sanbon-ro, Gunposhi, Gyeonggido, Republic of Korea.
authors.forename: Wongi
authors.initials: W
authors.lastname: Seol
authors.affiliation: Department of Biomedical Sciences, Neuroscience Graduate Program, Ajou University School of Medicine, Suwonshi, Gyeonggido, Republic of Korea.
authors.forename: Jin Hwan
authors.initials: JH
authors.lastname: Eun
authors.affiliation: InAm Neuroscience Research Center, Sanbon Medical Center, Collage of Medicine, Wonkwang University, 321 Sanbon-ro, Gunposhi, Gyeonggido, Republic of Korea; Department of Neurology, Sanbon Medical Center, Collage of Medicine, Wonkwang University, 321 Sanbon-ro, Gunposhi, Gyeonggido, Republic of Korea. Electronic address: sonih@wku.ac.kr.
authors.forename: Il-Hong
authors.initials: IH
authors.lastname: Son
mesh_terms: D000818:Animals; D002470:Cell Survival; D017077:Culture Media, Conditioned / Q000737:chemistry; D004195:Disease Models, Animal; D000068800:Etanercept / Q000737:chemistry; D007249:Inflammation; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000737:chemistry; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism; D010766:Phosphorylation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D000068800:Etanercept
keywords: LRRK2; Neuroinflammation; Parkinson's disease; p53