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The role of s-nitrosylation and s-glutathionylation of protein disulphide isomerase in protein misfolding and neurodegeneration.

Halloran M, Parakh S, Atkin JD - Int J Cell Biol (2013)

Bottom Line: However, an aberrant posttranslational modification of PDI, S-nitrosylation, inhibits its protective function in these conditions.S-nitrosylation is a redox-mediated modification that regulates protein function by covalent addition of nitric oxide- (NO-) containing groups to cysteine residues.Here, we discuss the evidence for abnormal S-nitrosylation of PDI (SNO-PDI) in neurodegeneration and how this may be linked to another aberrant modification of PDI, S-glutathionylation.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience in the School of Psychological Science, La Trobe University, Bundoora, VIC 3086, Australia.

ABSTRACT
Neurodegenerative diseases involve the progressive loss of neurons, and a pathological hallmark is the presence of abnormal inclusions containing misfolded proteins. Although the precise molecular mechanisms triggering neurodegeneration remain unclear, endoplasmic reticulum (ER) stress, elevated oxidative and nitrosative stress, and protein misfolding are important features in pathogenesis. Protein disulphide isomerase (PDI) is the prototype of a family of molecular chaperones and foldases upregulated during ER stress that are increasingly implicated in neurodegenerative diseases. PDI catalyzes the rearrangement and formation of disulphide bonds, thus facilitating protein folding, and in neurodegeneration may act to ameliorate the burden of protein misfolding. However, an aberrant posttranslational modification of PDI, S-nitrosylation, inhibits its protective function in these conditions. S-nitrosylation is a redox-mediated modification that regulates protein function by covalent addition of nitric oxide- (NO-) containing groups to cysteine residues. Here, we discuss the evidence for abnormal S-nitrosylation of PDI (SNO-PDI) in neurodegeneration and how this may be linked to another aberrant modification of PDI, S-glutathionylation. Understanding the role of aberrant S-nitrosylation/S-glutathionylation of PDI in the pathogenesis of neurodegenerative diseases may provide insights into novel therapeutic interventions in the future.

No MeSH data available.


Related in: MedlinePlus

Cell surface PDI, NO, and SNO-PDI. (A) Cell surface PDI reduces NO from extracellular SNO proteins (SNO-P) and in the process undergoes thiol modification. (B) Hyperactivation of the NMDAr leads to an intracellular influx of Ca2+ ions (NMDAr may also undergo reversible S-nitrosylation to ameliorate excessive activity). (C) Inhibition of mitochondria contributes to an increase in intracellular NO which is potentially oxidized by O2 leading to an increase in NO, nNOS, ROS, and RNS. (D) Increases in RNS/ROS alters the ER redox environment, and NO S-nitrosylates Ca2+ ryanodine (Ryn) receptor leading to a disruption in Ca2+ homeostasis. (E) ER-resident proteins such as PDI are vulnerable to S-nitrosylation, deactivating its isomerase and chaperone activity, leading to accumulation of misfolded proteins, ER stress, and UPR induction.
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fig2: Cell surface PDI, NO, and SNO-PDI. (A) Cell surface PDI reduces NO from extracellular SNO proteins (SNO-P) and in the process undergoes thiol modification. (B) Hyperactivation of the NMDAr leads to an intracellular influx of Ca2+ ions (NMDAr may also undergo reversible S-nitrosylation to ameliorate excessive activity). (C) Inhibition of mitochondria contributes to an increase in intracellular NO which is potentially oxidized by O2 leading to an increase in NO, nNOS, ROS, and RNS. (D) Increases in RNS/ROS alters the ER redox environment, and NO S-nitrosylates Ca2+ ryanodine (Ryn) receptor leading to a disruption in Ca2+ homeostasis. (E) ER-resident proteins such as PDI are vulnerable to S-nitrosylation, deactivating its isomerase and chaperone activity, leading to accumulation of misfolded proteins, ER stress, and UPR induction.

Mentions: One potential physiological mechanism of SNO-PDI production involves pathological hyperactivation of NMDAr [31] and inhibition of mitochondria leading to the generation of ROS, nNOS, and NO [31, 70, 71]. Exposure of cortical neurons to NMDA produces SNO-PDI, leading to an increase in polyubiquitinated proteins and apoptosis after 24 hrs of treatment. Furthermore, overexpression of WT PDI leads to a decrease in polyubiquitination and apoptosis, suggesting that PDI may provide protection against excitotoxicity from excessive stimulation of NMDA receptors [75]. Additionally, treatment with Rotenone, a mitochondrial complex inhibitor, produces elevated levels of SNO-PDI [75], suggesting that mitochondria are another source of NO or cytosolic nNOS [31]. NO disrupts Ca2+ homeostasis, potentially via S-nitrosylation of the ER Ca2+ channel ryanodine receptor, and induction of ER stress [57, 208]. ER-resident proteins are particularly vulnerable to S-nitrosylation and as such a positive feedback mechanism would create a scenario whereby excessive RNS/ROS increasingly deactivates protective ER-resident chaperones such as PDI, prolonging UPR activation, leading to increases in ROS/RNS generation eventually resulting in cell death [31]. ER dysfunction due to excessive oxidative/nitrosative stress may, thus, lead to the S-nitrosylation of PDI in neurodegenerative disease [31]. However, PDI family members PDIA1, PDIA3, and PDIA4 can be S-nitrosylated independently of UPR induction [209]. Alternatively, PDI located at the cell surface may also promote production of SNO proteins. It has been previously suggested that extracellular SNO proteins may transfer NO to the cytoplasm via the reducing activity of cell surface PDI [181, 182]. According to this theory, reduced NO may readily penetrate the plasma membrane, leading to SNO production [128] (Figure 2). Hence, the formation of SNO-PDI results in the abrogation of the normally protective isomerase/chaperone activity of PDI, which may contribute to protein misfolding and production of SNO proteins. This suggests that SNO-PDI may be a common pathological mechanism contributing to neurodegenerative diseases.


The role of s-nitrosylation and s-glutathionylation of protein disulphide isomerase in protein misfolding and neurodegeneration.

Halloran M, Parakh S, Atkin JD - Int J Cell Biol (2013)

Cell surface PDI, NO, and SNO-PDI. (A) Cell surface PDI reduces NO from extracellular SNO proteins (SNO-P) and in the process undergoes thiol modification. (B) Hyperactivation of the NMDAr leads to an intracellular influx of Ca2+ ions (NMDAr may also undergo reversible S-nitrosylation to ameliorate excessive activity). (C) Inhibition of mitochondria contributes to an increase in intracellular NO which is potentially oxidized by O2 leading to an increase in NO, nNOS, ROS, and RNS. (D) Increases in RNS/ROS alters the ER redox environment, and NO S-nitrosylates Ca2+ ryanodine (Ryn) receptor leading to a disruption in Ca2+ homeostasis. (E) ER-resident proteins such as PDI are vulnerable to S-nitrosylation, deactivating its isomerase and chaperone activity, leading to accumulation of misfolded proteins, ER stress, and UPR induction.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig2: Cell surface PDI, NO, and SNO-PDI. (A) Cell surface PDI reduces NO from extracellular SNO proteins (SNO-P) and in the process undergoes thiol modification. (B) Hyperactivation of the NMDAr leads to an intracellular influx of Ca2+ ions (NMDAr may also undergo reversible S-nitrosylation to ameliorate excessive activity). (C) Inhibition of mitochondria contributes to an increase in intracellular NO which is potentially oxidized by O2 leading to an increase in NO, nNOS, ROS, and RNS. (D) Increases in RNS/ROS alters the ER redox environment, and NO S-nitrosylates Ca2+ ryanodine (Ryn) receptor leading to a disruption in Ca2+ homeostasis. (E) ER-resident proteins such as PDI are vulnerable to S-nitrosylation, deactivating its isomerase and chaperone activity, leading to accumulation of misfolded proteins, ER stress, and UPR induction.
Mentions: One potential physiological mechanism of SNO-PDI production involves pathological hyperactivation of NMDAr [31] and inhibition of mitochondria leading to the generation of ROS, nNOS, and NO [31, 70, 71]. Exposure of cortical neurons to NMDA produces SNO-PDI, leading to an increase in polyubiquitinated proteins and apoptosis after 24 hrs of treatment. Furthermore, overexpression of WT PDI leads to a decrease in polyubiquitination and apoptosis, suggesting that PDI may provide protection against excitotoxicity from excessive stimulation of NMDA receptors [75]. Additionally, treatment with Rotenone, a mitochondrial complex inhibitor, produces elevated levels of SNO-PDI [75], suggesting that mitochondria are another source of NO or cytosolic nNOS [31]. NO disrupts Ca2+ homeostasis, potentially via S-nitrosylation of the ER Ca2+ channel ryanodine receptor, and induction of ER stress [57, 208]. ER-resident proteins are particularly vulnerable to S-nitrosylation and as such a positive feedback mechanism would create a scenario whereby excessive RNS/ROS increasingly deactivates protective ER-resident chaperones such as PDI, prolonging UPR activation, leading to increases in ROS/RNS generation eventually resulting in cell death [31]. ER dysfunction due to excessive oxidative/nitrosative stress may, thus, lead to the S-nitrosylation of PDI in neurodegenerative disease [31]. However, PDI family members PDIA1, PDIA3, and PDIA4 can be S-nitrosylated independently of UPR induction [209]. Alternatively, PDI located at the cell surface may also promote production of SNO proteins. It has been previously suggested that extracellular SNO proteins may transfer NO to the cytoplasm via the reducing activity of cell surface PDI [181, 182]. According to this theory, reduced NO may readily penetrate the plasma membrane, leading to SNO production [128] (Figure 2). Hence, the formation of SNO-PDI results in the abrogation of the normally protective isomerase/chaperone activity of PDI, which may contribute to protein misfolding and production of SNO proteins. This suggests that SNO-PDI may be a common pathological mechanism contributing to neurodegenerative diseases.

Bottom Line: However, an aberrant posttranslational modification of PDI, S-nitrosylation, inhibits its protective function in these conditions.S-nitrosylation is a redox-mediated modification that regulates protein function by covalent addition of nitric oxide- (NO-) containing groups to cysteine residues.Here, we discuss the evidence for abnormal S-nitrosylation of PDI (SNO-PDI) in neurodegeneration and how this may be linked to another aberrant modification of PDI, S-glutathionylation.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience in the School of Psychological Science, La Trobe University, Bundoora, VIC 3086, Australia.

ABSTRACT
Neurodegenerative diseases involve the progressive loss of neurons, and a pathological hallmark is the presence of abnormal inclusions containing misfolded proteins. Although the precise molecular mechanisms triggering neurodegeneration remain unclear, endoplasmic reticulum (ER) stress, elevated oxidative and nitrosative stress, and protein misfolding are important features in pathogenesis. Protein disulphide isomerase (PDI) is the prototype of a family of molecular chaperones and foldases upregulated during ER stress that are increasingly implicated in neurodegenerative diseases. PDI catalyzes the rearrangement and formation of disulphide bonds, thus facilitating protein folding, and in neurodegeneration may act to ameliorate the burden of protein misfolding. However, an aberrant posttranslational modification of PDI, S-nitrosylation, inhibits its protective function in these conditions. S-nitrosylation is a redox-mediated modification that regulates protein function by covalent addition of nitric oxide- (NO-) containing groups to cysteine residues. Here, we discuss the evidence for abnormal S-nitrosylation of PDI (SNO-PDI) in neurodegeneration and how this may be linked to another aberrant modification of PDI, S-glutathionylation. Understanding the role of aberrant S-nitrosylation/S-glutathionylation of PDI in the pathogenesis of neurodegenerative diseases may provide insights into novel therapeutic interventions in the future.

No MeSH data available.


Related in: MedlinePlus