title: Absence of glial α-dystrobrevin causes abnormalities of the blood-brain barrier and progressive brain edema.
abstract: The blood-brain barrier (BBB) plays a key role in maintaining brain functionality. Although mammalian BBB is formed by endothelial cells, its function requires interactions between endotheliocytes and glia. To understand the molecular mechanisms involved in these interactions is currently a major challenge. We show here that α-dystrobrevin (α-DB), a protein contributing to dystrophin-associated protein scaffolds in astrocytic endfeet, is essential for the formation and functioning of BBB. The absence of α-DB in null brains resulted in abnormal brain capillary permeability, progressively escalating brain edema, and damage of the neurovascular unit. Analyses in situ and in two-dimensional and three-dimensional in vitro models of BBB containing α-DB-null astrocytes demonstrated these abnormalities to be associated with loss of aquaporin-4 water and Kir4.1 potassium channels from glial endfeet, formation of intracellular vacuoles in α-DB-null astrocytes, and defects of the astrocyte-endothelial interactions. These caused deregulation of tight junction proteins in the endothelia. Importantly, α-DB but not dystrophins showed continuous expression throughout development in BBB models. Thus, α-DB emerges as a central organizer of dystrophin-associated protein in glial endfeet and a rare example of a glial protein with a role in maintaining BBB function. Its abnormalities might therefore lead to BBB dysfunction.
authors.affiliation: Molecular Medicine, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, United Kingdom.
authors.forename: Chun Fu
authors.initials: CF
authors.lastname: Lien
authors.forename: Sarajo Kumar
authors.initials: SK
authors.lastname: Mohanta
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Frontczak-Baniewicz
authors.forename: Jerome D
authors.initials: JD
authors.lastname: Swinny
authors.forename: Barbara
authors.initials: B
authors.lastname: Zablocka
authors.forename: Dariusz C
authors.initials: DC
authors.lastname: Górecki
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D018920:Coculture Techniques; D049029:Dystrophin-Associated Proteins / Q000502:physiology*; D004487:Edema / Q000473:pathology*; D004730:Endothelium, Vascular / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008858:Microscopy, Phase-Contrast / Q000379:methods; D009457:Neuroglia / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism; D000098854:Kcnj10 Channel
chemical_list: D051401:Aquaporin 4; D049029:Dystrophin-Associated Proteins; D000098854:Kcnj10 Channel; D024661:Potassium Channels, Inwardly Rectifying; C098885:dystrobrevin