Contribution of glutamatergic signaling to nitrosative stress-induced protein misfolding in normal brain aging and neurodegenerative diseases.
Glutamatergic hyperactivity, associated with Ca2+ influx and consequent production of nitric oxide (NO), is potentially involved in both normal brain aging and age-related neurodegenerative disorders. Many neurodegenerative diseases are characterized by conformational changes in proteins that result in their misfolding and aggregation. Normal protein degradation by the ubiquitin-proteasome system can prevent accumulation of aberrantly folded proteins. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. In particular, molecular chaperones - such as protein disulfide isomerase, glucose regulated protein 78, and heat shock proteins - can provide neuroprotection from misfolded proteins by facilitating proper folding and thus preventing aggregation. Here, we present evidence for the hypothesis that NO contributes to normal brain aging and degenerative conditions by S-nitrosylating specific chaperones that would otherwise prevent accumulation of misfolded proteins.
Nakamura
Tomohiro
T
Center for Neuroscience and Aging, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Gu
Zezong
Z
Lipton
Stuart A
SA
D000368:Aged; D000375:Aging; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D009584:Nitrogen / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D011489:Protein Denaturation; D019704:Protein Disulfide-Isomerases / Q000737:chemistry; D017510:Protein Folding; D015398:Signal Transduction
D005973:Glutamine; D009569:Nitric Oxide; D019704:Protein Disulfide-Isomerases; D009584:Nitrogen; D002118:Calcium