title: Astrocytes drive upregulation of the multidrug resistance transporter ABCB1 (P-Glycoprotein) in endothelial cells of the blood-brain barrier in mutant superoxide dismutase 1-linked amyotrophic lateral sclerosis.
abstract: The efficacy of drugs targeting the CNS is influenced by their limited brain access, which can lead to complete pharmacoresistance. Recently a tissue-specific and selective upregulation of the multidrug efflux transporter ABCB1 or P-glycoprotein (P-gp) in the spinal cord of both patients and the mutant SOD1-G93A mouse model of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease that prevalently kills motor neurons has been reported. Here, we extended the analysis of P-gp expression in the SOD1-G93A ALS mouse model and found that P-gp upregulation was restricted to endothelial cells of the capillaries, while P-gp expression was not detected in other cells of the spinal cord parenchyma such as astrocytes, oligodendrocytes, and neurons. Using both in vitro human and mouse models of the blood-brain barrier (BBB), we found that mutant SOD1 astrocytes were driving P-gp upregulation in endothelial cells. In addition, a significant increase in reactive oxygen species production, Nrf2 and NFκB activation in endothelial cells exposed to mutant SOD1 astrocytes in both human and murine BBB models were observed. Most interestingly, astrocytes expressing FUS-H517Q, a different familial ALS-linked mutated gene, also drove NFκB-dependent upregulation of P-gp. However, the pathway was not dependent on oxidative stress but rather involved TNF-α release. Overall, these findings indicated that nuclear translocation of NFκB was a converging mechanism used by endothelial cells of the BBB to upregulate P-gp expression in mutant SOD1-linked ALS and possibly other forms of familial ALS. GLIA 2016 GLIA 2016;64:1298-1313.
authors.affiliation: Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, Pennsylvania.
authors.forename: Hisham
authors.initials: H
authors.lastname: Qosa
authors.affiliation: Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, Pennsylvania.
authors.forename: Jessica
authors.initials: J
authors.lastname: Lichter
authors.affiliation: Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, Pennsylvania.
authors.forename: Mark
authors.initials: M
authors.lastname: Sarlo
authors.affiliation: Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, Pennsylvania.
authors.forename: Shashirekha S
authors.initials: SS
authors.lastname: Markandaiah
authors.affiliation: Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, Pennsylvania.
authors.forename: Kevin
authors.initials: K
authors.lastname: McAvoy
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, Maryland.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Richard
authors.affiliation: Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, Pennsylvania.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jablonski
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, Maryland.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Maragakis
authors.affiliation: Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, Pennsylvania.
authors.forename: Piera
authors.initials: P
authors.lastname: Pasinelli
authors.affiliation: Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, Pennsylvania.
authors.forename: Davide
authors.initials: D
authors.lastname: Trotti
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D018920:Coculture Techniques; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D000072105:Superoxide Dismutase-1 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016328:NF-kappa B; D034702:RNA-Binding Protein FUS; D000072105:Superoxide Dismutase-1; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C513055:ABCB1 protein, human; C000599550:FUS protein, human; C000599551:FUS protein, mouse; C000606290:SOD1 protein, human
keywords: P-glycoprotein; amyotrophic lateral sclerosis; blood-brain barrier; endothelial cells; mutant SOD1