title: PINK1 and its familial Parkinson's disease-associated mutation regulate brain vascular endothelial inflammation.
abstract: Parkinson's disease (PD) is a debilitating disorder that affects movement. Inflammation-mediated endothelial dysfunction has been found to be involved in neurodegenerative diseases, including PD. More than 40 PTEN-induced putative kinase 1 (PINK1) mutations have been found in PD patients. The effects of PINK1 in vascular inflammation are as yet unknown. In this study, our findings revealed that PINK1 can be increased by the inflammatory cytokine tumor necrosis factor-α in primary human brain microvascular endothelial cells (HBMECs). We found that wild-type PINK1 prevents expression of the adhesion molecule vascular cell adhesion molecule-1 (VCAM-1), thus inhibiting the attachment of monocytes to brain endothelial cells. However, PINK1G309D, the loss-of-function mutation associated with early-onset familial PD, promotes expression of VCAM-1 and exacerbates attachment of monocytes to brain endothelial cells. Mechanism studies revealed that overexpression of wild-type PINK1 inhibits the VCAM-1 promoter by inhibiting the transcriptional activity of interferon regulatory factor 1 (IRF-1). However, PINK1G309D promotes the VCAM-1 promoter by increasing the transcriptional activity of IRF-1.
authors.affiliation: Department of Neurology, Taihe Hospital of Hubei University of Medicine, No. 32, South Renmin Road, Shiyan, 442000, Hubei Province, China, yfwang1025@hotmail.com.
authors.forename: Wang
authors.initials: W
authors.lastname: Yunfu
authors.forename: Liu
authors.initials: L
authors.lastname: Guangjian
authors.forename: Zhong
authors.initials: Z
authors.lastname: Ping
authors.forename: Sun
authors.initials: S
authors.lastname: Yanpeng
authors.forename: Fang
authors.initials: F
authors.lastname: Xiaoxia
authors.forename: Hu
authors.initials: H
authors.lastname: Wei
authors.forename: Yuan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Hu
authors.initials: H
authors.lastname: Jingquan
authors.forename: Wang
authors.initials: W
authors.lastname: Songlin
authors.forename: Zhang
authors.initials: Z
authors.lastname: Hongyan
authors.forename: Liu
authors.initials: L
authors.lastname: Yong
authors.forename: Chen
authors.initials: C
authors.lastname: Shi
mesh_terms: D001921:Brain / Q000098:blood supply; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D050856:Interferon Regulatory Factor-1; D011494:Protein Kinases; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D000099202:PTEN-Induced Putative Kinase; C494257:IRF1 protein, human