title: ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration.
abstract: We report here that amyotrophic lateral sclerosis-linked superoxide dismutase 1 (SOD1) mutants with different biochemical characteristics disrupted the blood-spinal cord barrier in mice by reducing the levels of the tight junction proteins ZO-1, occludin and claudin-5 between endothelial cells. This resulted in microhemorrhages with release of neurotoxic hemoglobin-derived products, reductions in microcirculation and hypoperfusion. SOD1 mutant-mediated endothelial damage accumulated before motor neuron degeneration and the neurovascular inflammatory response occurred, indicating that it was a central contributor to disease initiation.
authors.affiliation: Center for Neurodegenerative and Vascular Brain Disorders and Department of Neurosurgery, University of Rochester Medical Center, Kornberg Medical Research Bldg., 601 Elmwood Avenue, Box 670, Rochester, New York 14642, USA.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Zhong
authors.forename: Rashid
authors.initials: R
authors.lastname: Deane
authors.forename: Zarina
authors.initials: Z
authors.lastname: Ali
authors.forename: Margaret
authors.initials: M
authors.lastname: Parisi
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Shapovalov
authors.forename: M Kerry
authors.initials: MK
authors.lastname: O'Banion
authors.forename: Konstantin
authors.initials: K
authors.lastname: Stojanovic
authors.forename: Abhay
authors.initials: A
authors.lastname: Sagare
authors.forename: Severine
authors.initials: S
authors.lastname: Boillee
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.forename: Berislav V
authors.initials: BV
authors.lastname: Zlokovic
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D002196:Capillaries / Q000201:enzymology* / Q000473:pathology; D062507:Claudin-5; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D006470:Hemorrhage / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009046:Motor Neurons / Q000473:pathology; D009410:Nerve Degeneration / Q000378:metabolism; D062793:Occludin; D010750:Phosphoproteins / Q000378:metabolism; D013116:Spinal Cord / Q000098:blood supply / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D019108:Tight Junctions / Q000201:enzymology / Q000473:pathology; D062826:Zonula Occludens-1 Protein
chemical_list: D062507:Claudin-5; C491511:Cldn5 protein, mouse; D007527:Isoenzymes; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D010750:Phosphoproteins; C000606290:SOD1 protein, human; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1