title: Cell death: protein misfolding and neurodegenerative diseases.
abstract: Several chronic neurodegenerative disorders manifest deposits of misfolded or aggregated proteins. Genetic mutations are the root cause for protein misfolding in rare families, but the majority of patients have sporadic forms possibly related to environmental factors. In some cases, the ubiquitin-proteasome system or molecular chaperones can prevent accumulation of aberrantly folded proteins. Recent studies suggest that generation of excessive nitric oxide (NO) and reactive oxygen species (ROS), in part due to overactivity of the NMDA-subtype of glutamate receptor, can mediate protein misfolding in the absence of genetic predisposition. S-Nitrosylation, or covalent reaction of NO with specific protein thiol groups, represents one mechanism contributing to NO-induced protein misfolding and neurotoxicity. Here, we present evidence suggesting that NO contributes to protein misfolding via S-nitrosylating protein-disulfide isomerase or the E3 ubiquitin ligase parkin. We discuss how memantine/NitroMemantine can inhibit excessive NMDA receptor activity to ameliorate NO production, protein misfolding, and neurodegeneration.
authors.affiliation: Center for Neuroscience, Aging and Stem Cell Research, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
mesh_terms: D016923:Cell Death; D006801:Humans; D008954:Models, Biological; 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
chemical_list: D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D019704:Protein Disulfide-Isomerases