Emerging roles of S-nitrosylation in protein misfolding and neurodegenerative diseases.
Overactivation of N-methyl-D-aspartate (NMDA)-type glutamate receptors accounts, at least in part, for excitotoxic neuronal damage, potentially contributing to a wide range of acute and chronic neurologic disorders. Recent studies have suggested that generation of excessive nitric oxide (NO) and reactive oxygen species (ROS) can mediate excitotoxicity, in part by triggering protein misfolding. S-Nitrosylation, which is a covalent reaction of a NO group with a cysteine thiol, represents one such mechanism that can contribute to NO-induced neurotoxicity. The ubiquitin-proteasome system (UPS), in conjunction with molecular chaperones, can prevent accumulation of aberrantly-folded proteins. For example, protein disulfide isomerase (PDI) can provide neuroprotection from misfolded proteins or endoplasmic reticulum stress through its molecular chaperone and thiol-disulfide oxidoreductase activities. Here, the authors present recent evidence suggesting that NO contributes to degenerative conditions by S-nitrosylating PDI (forming SNO-PDI) and the ubiquitin protein ligase, parkin (forming SNO-parkin). Moreover, it is demonstrated for the first time that inhibition of excessive NMDA receptor activity by memantine, via a mechanism of uncompetitive open-channel block with a relatively rapid off-rate, can ameliorate excessive production of NO, protein misfolding, and neurodegeneration.
Nakamura
Tomohiro
T
Center for Neuroscience and Aging, Burnham Institute for Medical Research, La Jolla, California 92039, USA.
Lipton
Stuart A
SA
D016923:Cell Death; D006801:Humans; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D015538:Nitrosation; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D017510:Protein Folding; D017382:Reactive Oxygen Species / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D019704:Protein Disulfide-Isomerases