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Cited by 238Amyotrophic Lateral Sclerosis ResearchBarrier Structure and Function StudiesSpinal Cord Injury Research

Blood–spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice

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Winkler, Ethan A., Sengillo, Jesse D., Sagare, Abhay P., Zhao, Zhen, Ma, Qingyi, Zuniga, Edward, Wang, Yaoming, Zhong, Zhihui +4 more·2014·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1401595111PMC PMC3964055
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Abstract

Significance: The blood–spinal cord barrier (BSCB) is damaged in human ALS and rodents expressing ALS-associated superoxide dismutase mutations. The role of BSCB breakdown in disease pathogenesis remains, however, unclear. Early motor-neuron dysfunction and injury are now shown to be proportional to the degree of BSCB disruption, and early protection of the BSCB integrity with an activated protein C analog is found to delay onset of motor-neuron impairment and degeneration. Altogether, these findings in mice show that BSCB breakdown plays a role in early-stage disease pathogenesis and that restoring BSCB integrity retards the disease process. These findings are relevant to the corresponding disease mechanism in human ALS in which ALS-associated vascular pathology is associated.

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Crossref · 10.1073/pnas.1401595111

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  • Studies in SOD1 transgenic mice expressing dismutase-active (G93A and G37R) and dismutase-inactive (G85R) mutations have suggested that BSCB breakdown occurs before motor neuron injury.

    “Studies in SOD1 transgenic mice expressing dismutase-active (G93A and G37R) and dismutase-inactive (G85R) mutations have suggested that BSCB breakdown occurs before motor neuron injury (194, 415, 651, 687, 688).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [651]

    The Results and Discussion report early BSCB breakdown contributing to motor-neuron injury in SOD1G93A mice, supporting the claim for that mutation. The Animals subsection of Materials and Methods identifies G93A mice as the study animals; our copy does not establish the same sequence in G37R or G85R transgenic mice or characterize the mutations by dismutase activity. No page numbers are available in our copy. (LLM, conf=0.88)

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  • SOD1 G93A mice develop ultrastructural capillary alterations, extravasation of red blood cells, and deposition of fibrin(ogen) and hemosiderin deposits in the brain stem and spinal cord early in the disease.

    “For instance, SOD1 G93A mice develop ultrastructural capillary alterations, extravasation of RBCs, and deposition of fibrin(ogen) and hemosiderin deposits in the brain stem and spinal cord early in the disease (194, 651, 687).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [651]

    The Results and Discussion report presymptomatic spinal-cord capillary barrier changes, erythrocyte extravasation, and hemosiderin deposits in SOD1G93A mice. Our copy does not establish the claimed ultrastructural capillary alterations or early fibrin(ogen) deposits in these mice, nor does it locate these findings in the brainstem. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Blood-brain barrier damage causing extravasation of red blood cells that leads to iron accumulation and oxidant stress can be successfully controlled by iron chelation therapy and/or antioxidant treatment, as shown in SOD1 G93A mutant mice with amyotrophic lateral sclerosis-like disease.

    “On the other hand, BBB damage causing extravasation of RBCs that leads to iron accumulation and oxidant stress can be successfully controlled by the iron chelation therapy and/or antioxidant treatment, as shown in SOD1 G93A mutant mice with ALS-like disease (651).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [651]

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  • Sealing the BBB reversed the course of motor neuron disorder in SOD1 G93A mutant ALS mice.

    “Similarly, sealing BBB reversed the course of motor neuron disorder in SOD1 G93A mutant ALS mice (651).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [651]

    The Results and Discussion report that restoring the blood–spinal cord barrier (BSCB) in SOD1G93A mice delayed motor impairment and prevented early degenerative changes. They do not report that sealing the blood–brain barrier (BBB) reversed the disease course; the paper says the contribution of BBB damage in these mice is unknown. Page numbers are not provided in our copy's passages. (LLM, conf=0.89)

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Cites

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Research works printed but not linked: 36

  1. [3]Winkler EA, et al. Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathol. 2013;125(1):111–120. doi: 10.1007/s00401-012-1039-8. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  2. [4]Henkel JS, Beers DR, Wen S, Bowser R, Appel SH. Decreased mRNA expression of tight junction proteins in lumbar spinal cords of patients with ALS. Neurology. 2009;72(18):1614–1616. doi: 10.1212/WNL.0b013e3181a41228. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  3. [5]Miyazaki K, et al. Disruption of neurovascular unit prior to motor neuron degeneration in amyotrophic lateral sclerosis. J Neurosci Res. 2011;89(5):718–728. doi: 10.1002/jnr.22594. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  4. [6]Oba H, et al. Amyotrophic lateral sclerosis: T2 shortening in motor cortex at MR imaging. Radiology. 1993;189(3):843–846. doi: 10.1148/radiology.189.3.8234713. [DOI] [PubMed] [Google Scholar] · DOI
  5. [7]Kwan JY, et al. Iron accumulation in deep cortical layers accounts for MRI signal abnormalities in ALS: Correlating 7 tesla MRI and pathology. PLoS ONE. 2012;7(4):e35241. doi: 10.1371/journal.pone.0035241. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  6. [8]Garbuzova-Davis S, et al. Evidence of compromised blood-spinal cord barrier in early and late symptomatic SOD1 mice modeling ALS. PLoS ONE. 2007;2(11):e1205. doi: 10.1371/journal.pone.0001205. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  7. [10]Nicaise C, et al. Impaired blood-brain and blood-spinal cord barriers in mutant SOD1-linked ALS rat. Brain Res. 2009;1301:152–162. doi: 10.1016/j.brainres.2009.09.018. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  8. [11]Zhong Z, et al. Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells. J Clin Invest. 2009;119(11):3437–3449. doi: 10.1172/JCI38476. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  9. [12]Miyazaki K, et al. Early and progressive impairment of spinal blood flow-glucose metabolism coupling in motor neuron degeneration of ALS model mice. J Cereb Blood Flow Metab. 2012;32(3):456–467. doi: 10.1038/jcbfm.2011.155. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  10. [13]Armulik A, et al. Pericytes regulate the blood-brain barrier. Nature. 2010;468(7323):557–561. doi: 10.1038/nature09522. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  11. [14]Bell RD, et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron. 2010;68(3):409–427. doi: 10.1016/j.neuron.2010.09.043. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  12. [16]Holbrook AM, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165(10):1095–1106. doi: 10.1001/archinte.165.10.1095. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  13. [17]Foerch C, et al. Experimental model of warfarin-associated intracerebral hemorrhage. Stroke. 2008;39(12):3397–3404. doi: 10.1161/STROKEAHA.108.517482. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  14. [18]Lauer A, et al. Anticoagulation with the oral direct thrombin inhibitor dabigatran does not enlarge hematoma volume in experimental intracerebral hemorrhage. Circulation. 2011;124(15):1654–1662. doi: 10.1161/CIRCULATIONAHA.111.035972. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  15. [19]Foerch C, You Z, Wang H, Lo EH, Whalen MJ. Traumatic brain injury during warfarin anticoagulation: An experimental study in mice. J Neurotrauma. 2012;29(6):1150–1155. doi: 10.1089/neu.2011.2104. [DOI] [PubMed] [Google Scholar] · DOI
  16. [20]Regan RF, Guo Y. Toxic effect of hemoglobin on spinal cord neurons in culture. J Neurotrauma. 1998;15(8):645–653. doi: 10.1089/neu.1998.15.645. [DOI] [PubMed] [Google Scholar] · DOI
  17. [22]Beers DR, et al. Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA. 2006;103(43):16021–16026. doi: 10.1073/pnas.0607423103. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  18. [23]Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K. Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci. 2007;10(5):608–614. doi: 10.1038/nn1885. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  19. [27]Gurney ME, et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science. 1994;264(5166):1772–1775. doi: 10.1126/science.8209258. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  20. [28]Clement AM, et al. Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science. 2003;302(5642):113–117. doi: 10.1126/science.1086071. [DOI] [PubMed] [Google Scholar] · DOI
  21. [29]Ferland G. Vitamin K and the nervous system: An overview of its actions. Adv Nutr. 2012;3(2):204–212. doi: 10.3945/an.111.001784. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  22. [30]Ezzi SA, Urushitani M, Julien JP. Wild-type superoxide dismutase acquires binding and toxic properties of ALS-linked mutant forms through oxidation. J Neurochem. 2007;102(1):170–178. doi: 10.1111/j.1471-4159.2007.04531.x. [DOI] [PubMed] [Google Scholar] · DOI
  23. [31]Gruzman A, et al. Common molecular signature in SOD1 for both sporadic and familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA. 2007;104(30):12524–12529. doi: 10.1073/pnas.0705044104. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  24. [32]Bosco DA, et al. Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nat Neurosci. 2010;13(11):1396–1403. doi: 10.1038/nn.2660. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  25. [33]Polymenidou M, Cleveland DW. The seeds of neurodegeneration: Prion-like spreading in ALS. Cell. 2011;147(3):498–508. doi: 10.1016/j.cell.2011.10.011. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  26. [34]Pokrishevsky E, et al. Aberrant localization of FUS and TDP43 is associated with misfolding of SOD1 in amyotrophic lateral sclerosis. PLoS ONE. 2012;7(4):e35050. doi: 10.1371/journal.pone.0035050. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  27. [35]Mosnier LO, Yang XV, Griffin JH. Activated protein C mutant with minimal anticoagulant activity, normal cytoprotective activity, and preservation of thrombin activable fibrinolysis inhibitor-dependent cytoprotective functions. J Biol Chem. 2007;282(45):33022–33033. doi: 10.1074/jbc.M705824200. [DOI] [PubMed] [Google Scholar] · DOI
  28. [37]Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway. Blood. 2007;109(8):3161–3172. doi: 10.1182/blood-2006-09-003004. [DOI] [PubMed] [Google Scholar] · DOI
  29. [38]Jeong SY, et al. Dysregulation of iron homeostasis in the CNS contributes to disease progression in a mouse model of amyotrophic lateral sclerosis. J Neurosci. 2009;29(3):610–619. doi: 10.1523/JNEUROSCI.5443-08.2009. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  30. [39]Guízar-Sahagún G, et al. Glutathione monoethyl ester improves functional recovery, enhances neuron survival, and stabilizes spinal cord blood flow after spinal cord injury in rats. Neuroscience. 2005;130(3):639–649. doi: 10.1016/j.neuroscience.2004.09.056. [DOI] [PubMed] [Google Scholar] · DOI
  31. [40]Vargas MR, Johnson DA, Johnson JA. Decreased glutathione accelerates neurological deficit and mitochondrial pathology in familial ALS-linked hSOD1(G93A) mice model. Neurobiol Dis. 2011;43(3):543–551. doi: 10.1016/j.nbd.2011.04.025. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  32. [41]Ralph GS, et al. Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model. Nat Med. 2005;11(4):429–433. doi: 10.1038/nm1205. [DOI] [PubMed] [Google Scholar] · DOI
  33. [42]Chang HC, et al. Modeling spinal muscular atrophy in Drosophila. PLoS ONE. 2008;3(9):e3209. doi: 10.1371/journal.pone.0003209. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  34. [43]Wang J, et al. Copper-binding-site-null SOD1 causes ALS in transgenic mice: Aggregates of non-native SOD1 delineate a common feature. Hum Mol Genet. 2003;12(21):2753–2764. doi: 10.1093/hmg/ddg312. [DOI] [PubMed] [Google Scholar] · DOI
  35. [44]Nilsson UA, Bassen M, Sävman K, Kjellmer I. A simple and rapid method for the determination of “free” iron in biological fluids. Free Radic Res. 2002;36(6):677–684. doi: 10.1080/10715760290029128. [DOI] [PubMed] [Google Scholar] · DOI
  36. [45]Cheng T, et al. Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage. Nat Med. 2006;12(11):1278–1285. doi: 10.1038/nm1498. [DOI] [PubMed] [Google Scholar] · DOI

Cited by

Sorted by citations

Authors
Winkler, E. A., Sengillo, J. D., Sagare, A. P., Zhao, Z., Ma, Q., Zuniga, E., Wang, Y., Zhong, Z., Sullivan, J. S., Griffin, J. H., Cleveland, D. W., & Zlokovic, B. V.
Affiliations
  • University of Southern California (US)
  • Sichuan University (CN)
  • Scripps Research Institute (US)
  • University of California San Diego (US)
  • Zilkha Neurogenetic Institute, Center for Neurodegeneration and Regeneration, Department of Physiology and Biophysics, University of Southern California, Los Angeles, CA 90089;
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2014-03-03
Volume
111
Issue
11
Pages
E1035-42
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1401595111
PMC
PMC3964055
OpenAlex
W2020061739
Cited by
238
References
9
Citations by year
2026: 13 · 2025: 15 · 2024: 19 · 2023: 17 · 2022: 21 · 2021: 33 · 2020: 13 · 2019: 14 · 2018: 18 · 2017: 20 · 2016: 24 · 2015: 22 · 2014: 8
FWCI
16.09
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • The Scholars Repository - LLU (Loma Linda University) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Wellcome Trust (089701)
  • National Institute on Aging (R01AG023084, R01AG039452, AG23084, R37AG023084, AG039452, P50AG005142)
  • National Heart, Lung, and Blood Institute (HL031950, HL052246, R01HL052246, R01HL021544, P01HL031950, R37HL052246)
  • National Institute of Neurological Disorders and Stroke (R37NS034467, NS 27036, NS34467, R37NS027036, R01NS034467, R01NS027036)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
Keywords
amyotrophic lateral sclerosis, blood-spinal cord barrier, blood-brain barrier disruption, motor neuron degeneration, SOD1 G93A mice, hemoglobin accumulation, iron accumulation, oxidative stress, microvascular lesions, warfarin, iron chelation, antioxidant treatment, neurodegeneration
MeSH terms
Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis, Animals, Ferrocyanides, Humans, Male, Mice, Transgenic, Motor Neurons, Nerve Degeneration, Protein C, Spinal Cord, Superoxide Dismutase, Warfarin, Immunoblotting, Point Mutation, Microscopy, Confocal, In Situ Nick-End Labeling, Rotarod Performance Test, Blood-Nerve Barrier, Mice, Real-Time Polymerase Chain Reaction, Tight Junction Proteins

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