ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration.
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.
Zhong
Zhihui
Z
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.
Deane
Rashid
R
Ali
Zarina
Z
Parisi
Margaret
M
Shapovalov
Yuriy
Y
O'Banion
M Kerry
MK
Stojanovic
Konstantin
K
Sagare
Abhay
A
Boillee
Severine
S
Cleveland
Don W
DW
Zlokovic
Berislav V
BV
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
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