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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Boillée, S., Vande Velde, C. & Cleveland, D.W. Neuron 52, 39–59 (2006).
Boillée, S. et al. Science 312, 1389–1392 (2006).
Garbuzova-Davis, S. et al. Brain Res. 1157, 126–137 (2007).
Garbuzova-Davis, S. et al. PLoS ONE 2, e1205 (2007).
Pun, S. et al. Nat. Neurosci. 9, 408–419 (2006).
Lobsiger, C.S., Boillée, S. & Cleveland, D.W. Proc. Natl. Acad. Sci. USA 104, 7319–7326 (2007).
Gurney, M.E. et al. Science 264, 1772–1775 (1994).
Zlokovic, B.V. Trends Neurosci. 28, 202–208 (2005).
Sargsyan, S.A., Monk, P.N. & Shaw, P.J. Glia 51, 241–253 (2005).
Hall, E.D., Oostveen, J.A. & Gurney, M.E. Glia 23, 249–256 (1998).
Oosthuyse, B. et al. Nat. Genet. 28, 131–138 (2001).
Lambrechts, D. et al. Nat. Genet. 34, 383–394 (2003).
Regan, R.F. & Guo, Y. J. Neurotrauma 15, 645–653 (1998).
Pasinelli, P., Borchelt, D.R., Houseweart, M.K., Cleveland, D.W. & Brown, R.H. Jr. Proc. Natl. Acad. Sci. USA 95, 15763–15768 (1998).
Brettschneider, J., Petzold, A., Süssmuth, S.D., Ludolph, A.C. & Tumani, H. Neurology 66, 852–856 (2006).
Acknowledgements
We thank K.L. Bentley of the Electron Microscopy Research Core at the University of Rochester for skillful processing of the electron microscopy samples. This work was supported by US National Institutes of Health grants R37 AG023084, R37 NS34467 and HL63290 to B.V.Z. and R37 NS27036 to D.W.C., and a Muscular Dystrophy Association grant to M.K.O. S.B. is supported by a development grant from the Muscular Dystrophy Association.
Author information
Authors and Affiliations
Contributions
Z.Z. conducted most of the experimental studies and co-designed some of the BSCB permeability studies with B.V.Z. R.D. supervised the regional blood flow studies and analyzed the data. Z.A. conducted the transmission electron microscopy study. M.P. carried out the blood flow studies. Y.S. and M.K.O. conducted immunostaining and RT-PCR studies for Icam-1 and Cox-2. K.S. carried out several immunostaining studies. A.S. performed the autoradiography studies. S.B. and D.W.C. provided essential experimental tools (SOD1G37R, SOD1G85R and SOD1WT mice) and expertise regarding various mouse models that express SOD1 mutants. D.W.C. provided critical input to the manuscript. B.V.Z. designed the entire study, supervised all portions of the study and wrote the manuscript.
Corresponding author
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–6 and Methods (PDF 2783 kb)
Rights and permissions
About this article
Cite this article
Zhong, Z., Deane, R., Ali, Z. et al. ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nat Neurosci 11, 420–422 (2008). https://doi.org/10.1038/nn2073
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn2073
This article is cited by
-
The therapeutic potential of probucol and probucol analogues in neurodegenerative diseases
Translational Neurodegeneration (2024)
-
Blood-spinal cord barrier disruption in degenerative cervical myelopathy
Fluids and Barriers of the CNS (2023)
-
Transplanted Human Bone Marrow Endothelial Progenitor Cells Prolong Functional Benefits and Extend Survival of ALS Mice Likely via Blood-Spinal Cord Barrier Repair
Stem Cell Reviews and Reports (2023)
-
The blood-brain barrier in aging and neurodegeneration
Molecular Psychiatry (2022)
-
Repeated infusion of mesenchymal stem cells maintain the condition to inhibit deteriorated motor function, leading to an extended lifespan in the SOD1G93A rat model of amyotrophic lateral sclerosis
Molecular Brain (2021)