From Reactive Oxygen and Nitrogen Species to Therapy
Published Online: 15 DEC 2009
Copyright © 2001 John Wiley & Sons, Ltd. All rights reserved.
How to Cite
McKercher, S. R., Nakamura, T. and Lipton, S. A. 2009. From Reactive Oxygen and Nitrogen Species to Therapy. eLS. .
- Published Online: 15 DEC 2009
Excessive free radicals, including reactive oxygen species (ROS) and nitric oxide (NO), contribute to pathological production of misfolded proteins, synaptic damage and apoptosis. Misfolded protein aggregates occur in several chronic neurodegenerative disorders, including Parkinson and Alzheimer diseases. In rare cases, the cause is a genetic mutation; the majority is sporadic and may be a response to environmental factors that generate free radicals. Overactivity of the N-methyl-d-aspartate (NMDA)-subtype of glutamate receptor can generate ROS and NO species that mediate protein misfolding, synaptic damage and apoptosis, and thus, neurodegenerative disease. We review current evidence that excessive ROS and NO contribute to protein misfolding by S-nitrosylation of the E3 ubiquitin ligase parkin and protein-disulfide isomerase. We also discuss NMDA receptor antagonists memantine and NitroMemantine, drugs that block excessive glutamate excitation, thereby limiting production of ROS and NO, and therapeutic electrophiles, drugs that protect cells from oxidative stress by activating the Nrf2 transcriptional pathway.
S-nitrosylation or transfer of the NO group to critical cysteine thiol can regulate protein function.
Under pathological circumstances, aberrant S-nitrosylation reactions can contribute to protein misfolding, neuronal injury and neurodegeneration.
- reactive oxygen species;
- molecular chaperone;
- ubiquitin-proteasome system;
- protein misfolding;