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.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyotrophic Lateral Sclerosis / enzymology*
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Amyotrophic Lateral Sclerosis / genetics
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Amyotrophic Lateral Sclerosis / pathology
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Animals
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Blood-Brain Barrier / metabolism*
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Blood-Brain Barrier / pathology
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Capillaries / enzymology*
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Capillaries / pathology
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Claudin-5
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Disease Progression
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Endothelium, Vascular / metabolism*
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Endothelium, Vascular / pathology
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Hemorrhage / pathology
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Humans
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Membrane Proteins / metabolism
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Mice
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Mice, Mutant Strains
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Motor Neurons / pathology
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Nerve Degeneration / metabolism
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Occludin
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Phosphoproteins / metabolism
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Spinal Cord / blood supply
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Spinal Cord / pathology
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Superoxide Dismutase / genetics
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Superoxide Dismutase / metabolism*
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Superoxide Dismutase-1
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Tight Junctions / enzymology
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Tight Junctions / pathology
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Zonula Occludens-1 Protein
Substances
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Claudin-5
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Cldn5 protein, mouse
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Isoenzymes
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Membrane Proteins
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OCLN protein, human
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Occludin
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Ocln protein, mouse
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Phosphoproteins
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SOD1 protein, human
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TJP1 protein, human
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Tjp1 protein, mouse
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Zonula Occludens-1 Protein
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Sod1 protein, mouse
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Superoxide Dismutase
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Superoxide Dismutase-1