Stress proteins located in the cytosol or endoplasmic reticulum (ER) maintain cell homeostasis and afford tolerance to severe insults1,2,3. In neurodegenerative diseases, several chaperones ameliorate the accumulation of misfolded proteins triggered by oxidative or nitrosative stress, or of mutated gene products4,5. Although severe ER stress can induce apoptosis2,6, the ER withstands relatively mild insults through the expression of stress proteins or chaperones such as glucose-regulated protein (GRP) and protein-disulphide isomerase (PDI), which assist in the maturation and transport of unfolded secretory proteins. PDI catalyses thiol–disulphide exchange, thus facilitating disulphide bond formation and rearrangement reactions7,8,9,10. PDI has two domains that function as independent active sites with homology to the small, redox-active protein thioredoxin7,8. During neurodegenerative disorders and cerebral ischaemia, the accumulation of immature and denatured proteins results in ER dysfunction11, but the upregulation of PDI represents an adaptive response to protect neuronal cells12,13,14. Here we show, in brains manifesting sporadic Parkinson's or Alzheimer's disease, that PDI is S-nitrosylated, a reaction transferring a nitric oxide (NO) group to a critical cysteine thiol to affect protein function15,16,17,18. NO-induced S-nitrosylation of PDI inhibits its enzymatic activity, leads to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response. S-Nitrosylation also abrogates PDI-mediated attenuation of neuronal cell death triggered by ER stress, misfolded proteins or proteasome inhibition. Thus, PDI prevents neurotoxicity associated with ER stress and protein misfolding, but NO blocks this protective effect in neurodegenerative disorders through the S-nitrosylation of PDI.
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We thank X. Fang for preparation of cerebrocortical cultures, T. William for technical assistance with the analysis of mass spectra, and R. Takahashi for the Pael receptor construct. T.U. was supported in part by the Mitsubishi Pharma Research Foundation and a Grant-in-Aid from the Ministry of Education, Culture, Sports and Technology of Japan. S.A.L. was supported in part by grants from the NIH, the American Parkinson's Disease Association, San Diego Chapter, and an Ellison Senior Scholars Award in Aging. Author Contributions T.U. and T.N. performed most of the experiments, contributing equally to the work, and helped to write the manuscript. D.Y., Z.Q.S. and Z.G. provided the biochemical data, and also contributed equally to the work. Y.M. analyzed the mass spectrometry data. E.M. provided the human subjects, and Y.N. provided constructs and advice. S.A.L., the senior author, designed the project, helped to analyse the data, wrote the manuscript and provided the financial support.
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Role of Nitric Oxide and Hydrogen Sulfide in Ischemic Stroke and the Emergent Epigenetic Underpinnings
Molecular Neurobiology (2018)