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ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration

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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.

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Figure 1: Breakdown of the BSCB with microhemorrhages in different SOD1 mutants presymptomatically.
Figure 2: SOD1 toxicity to the endothelium results in a loss of tight junction proteins and reductions in microcirculation and blood flow.

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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.

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Authors and Affiliations

  1. Center for Neurodegenerative and Vascular Brain Disorders and Departments of Neurosurgery and Neurology, University of Rochester Medical Center, Kornberg Medical Research Bldg., 601 Elmwood Avenue, Box 670, Rochester, 14642, New York, USA

    Zhihui Zhong, Rashid Deane, Zarina Ali, Margaret Parisi, Konstantin Stojanovic, Abhay Sagare & Berislav V Zlokovic

  2. Department of Neurobiology and Anatomy, University of Rochester Medical Center, 601 Elmwood Avenue, Box 603, Rochester, 14642, New York, USA

    Yuriy Shapovalov & M Kerry O'Banion

  3. Ludwig Institute for Cancer Research and Departments of Medicine and Neuroscience, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093-0670, California, USA

    Severine Boillee & Don W Cleveland

Authors
  1. Zhihui Zhong
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  2. Rashid Deane
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  3. Zarina Ali
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  4. Margaret Parisi
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  5. Yuriy Shapovalov
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  6. M Kerry O'Banion
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  7. Konstantin Stojanovic
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  8. Abhay Sagare
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  9. Severine Boillee
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  10. Don W Cleveland
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  11. Berislav V Zlokovic
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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

Correspondence to Berislav V Zlokovic.

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Supplementary Figures 1–6 and Methods (PDF 2783 kb)

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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

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