Glyceraldehyde-3-phosphate Dehydrogenase, the Putative Target of the Antiapoptotic Compounds CGP 3466 and R-(−)-Deprenyl

Kragten, Eddy A.; Lalande, Isabelle; Zimmermann, Kaspar; Roggo, Silvio; Schindler, Patrick; Müller, Dieter; Oostrum, Jan van; Waldmeier, P. C.; Fürst, Peter

doi:10.1074/jbc.273.10.5821

Cited by 199 publications

(137 citation statements)

References 43 publications

(38 reference statements)

Supporting

Mentioning

127

Contrasting

Unclassified

Order By: Relevance

“…However, anti-inflammatory drugs that specifically target the caspase-1 pathway, such as minocycline [70], might represent a new treatment strategy. Treatment with R-(−)-Deprenyl, a monoamine oxidase-B inhibitor, prevents hyperglycemia-induced nuclear translocation and accumulation of GAPDH in the Müller cells [55] and classes of these drugs might be beneficial of treating diabetic retinopathy although more studies are needed.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Nuclear GAPDH: changing the fate of Müller cells in diabetes

Jayaguru

Mohr

2011

j ocul biol dis inform

View full text Add to dashboard Cite

Müller cells, the primary glial cells are a crucial component of the retinal tissue performing a wide range of functions including maintaining the blood-retinal barrier. Several studies suggest that diabetes leads to Müller cell dysfunction and loss. The pathophysiology of hyperglycemiainduced cellular injury of Müller cells remains only poorly understood. Recently, the concept that translocation of the predominantly cytosolic glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to the nucleus and its accumulation in this cellular compartment alters transcriptional events associated with cell death induction has gained major interest. High glucose conditions induce nuclear translocation and accumulation of GAPDH in the nucleus of Müller cells in vivo and in vitro. With regards to Müller cell dysfunction, the effects of nuclear accumulation of GAPDH are multifaceted. Considering the functional versatility of GAPDH including gene regulation, DNA repair, telomere protection, etc., it is of immense importance to explore possible GAPDH actions to unravel the mysteries around the role of GAPDH in hyperglycemia-induced cellular changes in order to develop novel therapeutic strategies. Therefore, this review focuses on the molecular events associated with the nuclear translocation of GAPDH and how it affects the fate of Müller cells in diabetes.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Studies in different systems show that GAPDH translocates to the nucleus under certain stress conditions and that this event is associated with cell death [52][53][54][55][56][57]. GAPDH interacts with the E3 ubiquitin ligase SIAH1 (seven in absentia homolog 1) to translocate to the nucleus [58].…”

Section: Nuclear Gapdh and Cell Deathmentioning

confidence: 99%

Nuclear GAPDH: changing the fate of Müller cells in diabetes

Jayaguru

Mohr

2011

j ocul biol dis inform

View full text Add to dashboard Cite

show abstract

“…106 Initially, the effects of Deprenyl were thought to depend on inhibition of monoamine oxidase-B (MAO-B); however, recent research has suggested that Deprenyl increases survival of dopaminergic neurons independently of MAO-B inhibition, and GAPDH represents a possible target for the beneficial effect of Deprenyl. 107 It is postulated that the binding of Deprenyl to GAPDH interferes with the formation of SNO-GAPDH and its interaction with Siah1, thereby affording neuroprotection.…”

Section: S-nitrosylation As a Potential Positive Regulator Of Excitotmentioning

confidence: 99%

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

Nakamura

Lipton

2007

Cell Death Differ

View full text Add to dashboard Cite

Although activation of glutamate receptors is essential for normal brain function, excessive activity leads to a form of neurotoxicity known as excitotoxicity. Key mediators of excitotoxic damage include overactivation of N-methyl-D-aspartate (NMDA) receptors, resulting in excessive Ca 2 þ influx with production of free radicals and other injurious pathways. Overproduction of free radical nitric oxide (NO) contributes to acute and chronic neurodegenerative disorders. NO can react with cysteine thiol groups to form S-nitrosothiols and thus change protein function. S-nitrosylation can result in neuroprotective or neurodestructive consequences depending on the protein involved. Many neurodegenerative diseases manifest conformational changes in proteins that result in misfolding and aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Molecular chaperones -such as protein-disulfide isomerase, glucose-regulated protein 78, and heat-shock proteins -can provide neuroprotection by facilitating proper protein folding. Here, we review the effect of S-nitrosylation on protein function under excitotoxic conditions, and present evidence that NO contributes to degenerative conditions by S-nitrosylating-specific chaperones that would otherwise prevent accumulation of misfolded proteins and neuronal cell death. In contrast, we also review therapeutics that can abrogate excitotoxic damage by preventing excessive NMDA receptor activity, in part via S-nitrosylation of this receptor to curtail excessive activity.

show abstract

“…CGP3466B is a compound related to the anti-Parkinson's drug R-(-)-deprenyl, which has antiapoptotic effects on the human neuroblastoma cell line PUJA [9] and upregulates Pcmt1 expression in rat astroglial cell cultures [8]. In addition, transfection of mouse cortical cells with Pcmt1 protects against apoptosis [8].…”

Section: Discussionmentioning

confidence: 99%

Post-translational protein modifications in type 1 diabetes: a role for the repair enzyme protein-l-isoaspartate (d-aspartate) O-methyltransferase?

Wagner

Cloos²,

Bergholdt

et al. 2007

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis Post-translational modifications, such as isomerisation of native proteins, may create new antigenic epitopes and play a role in the development of the autoimmune response. Protein-L-isoaspartate (D-aspartate) O-methyltransferase (PIMT), encoded by the gene PCMT1, is an enzyme that recognises and repairs isomerised Asn and Asp residues in proteins. The aim of this study was to assess the role of PIMT in the development of type 1 diabetes. Materials and methods Immunohistochemical analysis of 59 normal human tissues was performed with a monoclonal PIMT antibody. CGP3466B, which induces expression of Pcmt1, was tested on MIN6 and INS1 cells, to assess its effect on Pcmt1 mRNA and PIMT levels (RT-PCR and western blot) and apoptosis. Forty-five diabetes-prone BioBreeding (BB) Ottawa Karlsburg (OK) rats were randomised to receive 0, 14 or 500 μg/kg (denoted as the control, low-dose and high-dose group, respectively) of CGP3466B from week 5 to week 20. Results A high level of PIMT protein was detected in beta cells. CGP3466B induced a two-to threefold increase in Pcmt1 mRNA levels and reduced apoptosis by 10% in MIN6 cells. No significant effect was seen on cytokineinduced apoptosis or PIMT protein levels in INS1 cells. The onset of diabetes in the BB/OK rats was significantly delayed (85.6±9.0 vs 84.3±6.8 vs 106.6±13.5 days, respectively; p<0.01 for high-dose vs low-dose and control groups), the severity of the disease was reduced (glucose 22.2±3.2 vs 16.9±2.6 vs 15.8±2.7 mmol; p<0.01 for high-and low-dose groups vs control group) and residual beta cells were more frequently identified (43% vs 71% vs 86%; p<0.05 for high-dose vs control group) in the treated animals. Conclusions/interpretation The results support a role for post-translational modifications and PIMT in the development of type 1 diabetes in the diabetes-prone BB rat, and perhaps also in humans.

show abstract

Glyceraldehyde-3-phosphate Dehydrogenase, the Putative Target of the Antiapoptotic Compounds CGP 3466 and R-(−)-Deprenyl

Abstract: R-(؊)-Deprenyl

Cited by 199 publications

References 43 publications

Nuclear GAPDH: changing the fate of Müller cells in diabetes

Nuclear GAPDH: changing the fate of Müller cells in diabetes

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

Post-translational protein modifications in type 1 diabetes: a role for the repair enzyme protein-l-isoaspartate (d-aspartate) O-methyltransferase?

Contact Info

Product

Resources

About