Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 12, Pages E1102-E1111Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1215177110
Keywords
apoptosis; peroxynitrite; PC12 cells
Categories
Funding
- National Institutes of Health (NIH)/National Center for Research Resources Shared Instrumentation Grant [RR06487, R13795]
- National Cancer Institute Core Support Grant [P30 CA13148]
- Burke Medical Research Institute
- New York State Spinal Cord Injury Center of Research
- NIH [NS36761, NS42834, NS058628, AT002034, ES00210]
- ALS Association
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Oxidative stress is a widely recognized cause of cell death associated with neurodegeneration, inflammation, and aging. Tyrosine nitration in these conditions has been reported extensively, but whether tyrosine nitration is a marker or plays a role in the cell-death processes was unknown. Here, we show that nitration of a single tyrosine residue on a small proportion of 90-kDa heat-shock protein (Hsp90), is sufficient to induce motor neuron death by the P2X7 receptor-dependent activation of the Fas pathway. Nitrotyrosine at position 33 or 56 stimulates a toxic gain of function that turns Hsp90 into a toxic protein. Using an antibody that recognizes the nitrated Hsp90, we found immunoreactivity in motor neurons of patients with amyotrophic lateral sclerosis, in an animal model of amyotrophic lateral sclerosis, and after experimental spinal cord injury. Our findings reveal that cell death can be triggered by nitration of a single protein and highlight nitrated Hsp90 as a potential target for the development of effective therapies for a large number of pathologies.
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