title: α-Synuclein pre-formed fibrils impair tight junction protein expression without affecting cerebral endothelial cell function.
abstract: Recently it has been shown that there is impaired cerebral endothelial function in many chronic neurodegenerative disorders including Alzheimer's and Huntington's disease. Such problems have also been reported in Parkinson's disease, in which α-synuclein aggregation is the pathological hallmark. However, little is known about the relationship between misfolded α-synuclein and endothelial function. In the present study, we therefore examined whether α-synuclein preformed fibrils affect endothelial function in vitro. Using a well-established endothelial cell model, we found that the expression of tight junction proteins, in particular zona occludens-1 and occludin, was significantly perturbed in the presence of fibril-seeded neurotoxicity. Disrupted expression of these proteins was also found in the postmortem brains of patients dying with Parkinson's disease. There was though little evidence in vitro of functional impairments in endothelial cell function in terms of transendothelial electrical resistance and permeability. This study therefore shows for the first time that misfolded α-synuclein can interact and affect the cerebral endothelial system, although its relevance to the pathogenesis of Parkinson's disease remains to be elucidated.
authors.affiliation: John van Geest Centre for Brain Repair and Department of Clinical Neuroscience, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, United Kingdom. Electronic address: wlk21@cam.ac.uk.
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Kuan
authors.affiliation: John van Geest Centre for Brain Repair and Department of Clinical Neuroscience, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, United Kingdom; Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, United States.
authors.forename: Neal
authors.initials: N
authors.lastname: Bennett
authors.affiliation: John van Geest Centre for Brain Repair and Department of Clinical Neuroscience, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, United Kingdom.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: He
authors.affiliation: Cambridge Advanced Imaging Centre, Department of Physiology, Development and Neuroscience, Anatomy Building, University of Cambridge, Downing Street, Cambridge CB2 3DY, United Kingdom.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Skepper
authors.affiliation: John van Geest Centre for Brain Repair and Department of Clinical Neuroscience, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, United Kingdom.
authors.forename: Nataly
authors.initials: N
authors.lastname: Martynyuk
authors.affiliation: John van Geest Centre for Brain Repair and Department of Clinical Neuroscience, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, United Kingdom.
authors.forename: Ruwani
authors.initials: R
authors.lastname: Wijeyekoon
authors.affiliation: Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, United States; Department of Chemical & Biochemical Engineering, Rutgers University, Piscataway, NJ, United States.
authors.forename: Prabhas V
authors.initials: PV
authors.lastname: Moghe
authors.affiliation: John van Geest Centre for Brain Repair and Department of Clinical Neuroscience, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, United Kingdom.
authors.forename: Caroline H
authors.initials: CH
authors.lastname: Williams-Gray
authors.affiliation: John van Geest Centre for Brain Repair and Department of Clinical Neuroscience, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, United Kingdom; Department of Neurology, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Barker
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000648:ultrastructure; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D017097:Electric Impedance; D042783:Endothelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D005333:Fetus; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D062793:Occludin / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology*; D018709:Statistics, Nonparametric; D019108:Tight Junctions / Q000378:metabolism* / Q000648:ultrastructure; D013997:Time Factors; D062826:Zonula Occludens-1 Protein / Q000378:metabolism; D051844:alpha-Synuclein
chemical_list: D000682:Amyloid; D016207:Cytokines; D009419:Nerve Tissue Proteins; D062793:Occludin; D062826:Zonula Occludens-1 Protein; D051844:alpha-Synuclein
keywords: Blood-brain barrier; Occludin; Parkinson's disease; Permeability; Transendothelial electrical resistance; Zona occludens-1; α-Synuclein preformed fibrils