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

  title={S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration},
  author={Takashi Uehara and Tomohiro Nakamura and Dongdong Yao and Zhong-Qing Shi and Zezong Gu and Yuliang Ma and Eliezer Masliah and Yasuyuki Nomura and Stuart A. Lipton},
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… 

Accumulation of misfolded protein through nitrosative stress linked to neurodegenerative disorders.

  • T. Uehara
  • Biology
    Antioxidants & redox signaling
  • 2007
The focus of this review is the identity of the target of NO, a free radical gas, which is reported to be involved in such processes as vasorelaxation and neurotransmission and implicated in neuronal cell death or neurodegeneration.

The Role of S-Nitrosylation and S-Glutathionylation of Protein Disulphide Isomerase in Protein Misfolding and Neurodegeneration

The evidence for abnormal S-nitrosylation of PDI (SNO-PDI) in neurodegeneration is discussed and how this may be linked to another aberrant modification ofPDI, S-glutathionylation.

Molecular mechanisms of nitrosative stress-mediated protein misfolding in neurodegenerative diseases

Evidence is presented for the hypothesis that nitric oxide contributes to degenerative conditions by S-nitrosylating specific chaperones or UPS proteins that would otherwise prevent accumulation of misfolded proteins.

Nitrosative stress-induced S-glutathionylation of protein disulfide isomerase.

S-nitrosylation of the thioredoxin-like domains of protein disulfide isomerase and its role in neurodegenerative conditions

This review will focus on the importance of the thioredoxin-like CGHC active site of PDI and how the understanding of this structural motif will play a key role in unraveling the pathogenic mechanisms that underpin these neurodegenerative conditions.

Emerging roles of S-nitrosylation in protein misfolding and neurodegenerative diseases.

It is demonstrated for the first time that inhibition of excessive NMDA receptor activity by memantine, via a mechanism of uncompetitive open-channel block with a relatively rapid off-rate, can ameliorate excessive production of NO, protein misfolding, and neurodegeneration.

S-nitrosylation of critical protein thiols mediates protein misfolding and mitochondrial dysfunction in neurodegenerative diseases.

Examples of S-nitrosylated proteins that regulate misfolded protein accumulation and mitochondrial dynamics are highlighted, including parkin, a ubiquitin E3 ligase and neuroprotective molecule, and protein-disulfide isomerase, a chaperone enzyme for nascent protein folding.

The Unfolded Protein Response and the Role of Protein Disulfide Isomerase in Neurodegeneration

This review will focus on the evidence linking ER stress and the UPR to neurodegenerative diseases, with particular emphasis on the emerging functions ascribed to PDI in these conditions.

Thioredoxin-interacting protein regulates protein disulfide isomerases and endoplasmic reticulum stress

Thioredoxin‐interacting protein (Txnip), a member of the arrestin protein superfamily and one of the most strongly induced proteins in diabetic patients, regulates PDI activity and UPR signaling and is found to binds to PDIs and increases their enzymatic activity.



Role of Ubiquilin Associated with Protein-disulfide Isomerase in the Endoplasmic Reticulum in Stress-induced Apoptotic Cell Death*

It is reported that protein-disulfide isomerase interacts with ubiquilin, which has a ubiquitin-like domain and a Ubiquilin-associated domain and is also up-regulated in response to hypoxia in glial cells with a time course similar to that of PDI induction.

Endoplasmic Reticulum Stress and the Unfolded Protein Response in Cellular Models of Parkinson's Disease

Serial analysis of gene expression on neuronal PC12 cells exposed to 6-hydroxydopamine revealed a striking increase in transcripts associated with the unfolded protein response, raising the possibility of widespread involvement of endoplasmic reticulum stress and the unfoldedprotein response in the pathophysiology of this disease.

Sequence of protein disulphide isomerase and implications of its relationship to thioredoxin

The sequence of cloned rat liver PDI complementary DNA is described which predicts a protein with two distinct regions homologous with Escherichia coli thioredoxin, a known cofactor in oxidation–reduction reactions, suggesting that PDI, similar in action to thiOREDoxin, catalyses disulphide bond interchange via an internal disulPHide–sulphydryl interchange.

Up-regulation of Protein-disulfide Isomerase in Response to Hypoxia/Brain Ischemia and Its Protective Effect against Apoptotic Cell Death*

It is suggested that up-regulated PDI may play a critical role in resistance to ischemic damage, and that the elevation of levels of this protein in the brain may have beneficial effects against brain stroke.

Characterization of the S-Denitrosation Activity of Protein Disulfide Isomerase*

The present demonstration that PDI can be S-nitrosated and thatPDI-SNO can be denitrosated by PDI suggests that this enzyme could be intimately involved in the transport of intracellular NO equivalents to the cell surface as well as the previous demonstration of PDI in the transfer of S- Nitrosothiol-bound NO to the cytosol.