Brief Communication abstract


Nature Neuroscience 11, 420 - 422 (2008)
Published online: 16 March 2008 | doi:10.1038/nn2073

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

Zhihui Zhong1, Rashid Deane1, Zarina Ali1, Margaret Parisi1, Yuriy Shapovalov2, M Kerry O'Banion2, Konstantin Stojanovic1, Abhay Sagare1, Severine Boillee3, Don W Cleveland3 & Berislav V Zlokovic1

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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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  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, New York 14642, USA.
  2. Department of Neurobiology and Anatomy, University of Rochester Medical Center, 601 Elmwood Avenue, Box 603, Rochester, New York 14642, USA.
  3. Ludwig Institute for Cancer Research and Departments of Medicine and Neuroscience, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093-0670, USA.

Correspondence to: Berislav V Zlokovic1 e-mail: berislav_zlokovic@urmc.rochester.edu



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