title: Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice.
abstract: Humans with ALS and transgenic rodents expressing ALS-associated superoxide dismutase (SOD1) mutations develop spontaneous blood-spinal cord barrier (BSCB) breakdown, causing microvascular spinal-cord lesions. The role of BSCB breakdown in ALS disease pathogenesis in humans and mice remains, however, unclear, although chronic blood-brain barrier opening has been shown to facilitate accumulation of toxic blood-derived products in the central nervous system, resulting in secondary neurodegenerative changes. By repairing the BSCB and/or removing the BSCB-derived injurious stimuli, we now identify that accumulation of blood-derived neurotoxic hemoglobin and iron in the spinal cord leads to early motor-neuron degeneration in SOD1(G93A) mice at least in part through iron-dependent oxidant stress. Using spontaneous or warfarin-accelerated microvascular lesions, motor-neuron dysfunction and injury were found to be proportional to the degree of BSCB disruption at early disease stages in SOD1(G93A) mice. Early treatment with an activated protein C analog restored BSCB integrity that developed from spontaneous or warfarin-accelerated microvascular lesions in SOD1(G93A) mice and eliminated neurotoxic hemoglobin and iron deposits. Restoration of BSCB integrity delayed onset of motor-neuron impairment and degeneration. Early chelation of blood-derived iron and antioxidant treatment mitigated early motor-neuronal injury. Our data suggest that BSCB breakdown contributes to early motor-neuron degeneration in ALS mice and that restoring BSCB integrity during an early disease phase retards the disease process.
authors.affiliation: Zilkha Neurogenetic Institute, Center for Neurodegeneration and Regeneration, Department of Physiology and Biophysics, University of Southern California, Los Angeles, CA 90089.
authors.forename: Ethan A
authors.initials: EA
authors.lastname: Winkler
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Sengillo
authors.forename: Abhay P
authors.initials: AP
authors.lastname: Sagare
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Ma
authors.forename: Edward
authors.initials: E
authors.lastname: Zuniga
authors.forename: Yaoming
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Zhong
authors.forename: John S
authors.initials: JS
authors.lastname: Sullivan
authors.forename: John H
authors.initials: JH
authors.lastname: Griffin
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 / Q000503:physiopathology*; D000818:Animals; D049428:Blood-Nerve Barrier / Q000473:pathology* / Q000502:physiology; D005295:Ferrocyanides; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009046:Motor Neurons / Q000473:pathology* / Q000502:physiology; D009410:Nerve Degeneration / Q000503:physiopathology*; D017354:Point Mutation / Q000235:genetics; D011486:Protein C / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D045442:Rotarod Performance Test; D013116:Spinal Cord / Q000473:pathology* / Q000502:physiology; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D062725:Tight Junction Proteins / Q000235:genetics / Q000378:metabolism; D014859:Warfarin
chemical_list: D005295:Ferrocyanides; D011486:Protein C; C000606290:SOD1 protein, human; D062725:Tight Junction Proteins; D014859:Warfarin; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C000170:ferric ferrocyanide
keywords: amyotrophic lateral sclerosis; neurodegeneration