Open AccessContribution of glutamatergic signaling to nitrosative stress‐induced protein misfolding in normal brain aging and neurodegenerative diseases
Author(s) -
Nakamura Tomohiro,
Gu Zezong,
Lipton Stuart A.
Publication year - 2007
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/j.1474-9726.2007.00284.x
Subject(s) - proteostasis , protein folding , neuroprotection , biology , protein aggregation , proteasome , neurodegeneration , glutamatergic , heat shock protein , aggresome , microbiology and biotechnology , biochemistry , ubiquitin , neuroscience , glutamate receptor , disease , medicine , receptor , gene
Summary Glutamatergic hyperactivity, associated with Ca 2+ 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.