S -Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration

• Published in: Nature 2006-05, Vol.441 (7092), p.513-517
• Main Authors: Nakamura, Tomohiro, Shi, Zhong-Qing, Lipton, Stuart A, Uehara, Takashi, Masliah, Eliezer, Nomura, Yasuyuki, Ma, Yuliang, Yao, Dongdong, Gu, Zezong
• Format: Article
• Language: English
• Subjects: Accumulation; Alzheimer Disease - enzymology; Alzheimer Disease - metabolism; Alzheimer's disease; Animals; Apoptosis; Attenuation; Binding Sites; Biological and medical sciences; Cell death; Cell Line; Chaperones; Cysteine - metabolism; Cytosol; Degeneration; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disorders; Disulfides; Domains; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Enzymatic activity; Genetics; Health aspects; Heat shock proteins; Homeostasis; Homology; Humanities and Social Sciences; Humans; Ischemia; Isomerases; letter; Medical sciences; Molecular Chaperones - metabolism; Movement disorders; multidisciplinary; Mutation; N-Methylaspartate - pharmacology; Nervous system; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - enzymology; Neurodegenerative Diseases - metabolism; Neurological diseases; Neurological disorders; Neurology; Neurotoxicity; Nitric oxide; Nitric Oxide - metabolism; Parkinson Disease - enzymology; Parkinson Disease - metabolism; Parkinson's disease; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors; Proteasomes; Protein Disulfide-Isomerases - chemistry; Protein Disulfide-Isomerases - genetics; Protein Disulfide-Isomerases - metabolism; Protein Folding; Proteins; Receptors, G-Protein-Coupled - metabolism; Science; Science (multidisciplinary); Stress; Stress proteins; Sulfhydryl Compounds - metabolism; Thioredoxin; Ubiquitin - metabolism
• ISSN: 0028-0836; 1476-4687; 1476-4679
• DOI: 10.1038/nature04782

Stress proteins located in the cytosol or endoplasmic reticulum (ER) maintain cell homeostasis and afford tolerance to severe insults. In neurodegenerative diseases, several chaperones ameliorate the accumulation of misfolded proteins triggered by oxidative or nitrosative stress, or of mutated gene products. Although severe ER stress can induce apoptosis, 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 reactions. PDI has two domains that function as independent active sites with homology to the small, redox-active protein thioredoxin. During neurodegenerative disorders and cerebral ischaemia, the accumulation of immature and denatured proteins results in ER dysfunction, but the upregulation of PDI represents an adaptive response to protect neuronal cells. 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 function. 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.