Glyceraldehyde-3-phosphate dehydrogenase: Nuclear translocation participates in neuronal and nonneuronal cell death

Sawa, Akira; Khan, Adil Aziz; Hester, Lynda D.; Snyder, Solomon H.

doi:10.1073/pnas.94.21.11669

Cited by 305 publications

(230 citation statements)

References 43 publications

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“…25,26 Our pioneering studies show that GAPDH overexpression and nuclear translocation is involved in apoptosis of several cell types subjected to various insults. 16,[18][19][20]27 This role of GAPDH in apoptosis is supported by these studies, which demonstrate that GAPDH antisense oligonucleotides suppress GAPDH overexpression and nuclear translocation and protect cells from apoptotic insults. In addition, CGP 3466, a deprenyl derivative, which binds GAPDH, also blocks growth factor deprivation-induced GAPDH nuclear translocation and apoptosis.…”

Section: Discussionmentioning

confidence: 65%

“…Precise mechanisms underlying GAPDH nuclear translocation-mediated apoptosis are unclear, but could be related to a decrease in GAPDH-associated functions such as glycolytic and uracil DNA glycosylase activities following nuclear translocation, 27 or due to interaction with nuclear proteins and alterations in nuclear function in a gain-oftoxicity manner. 20,29 One such nuclear protein that can possibly interact with GAPDH is NcoR (A Sawa et al unpublished results).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that nuclear translocation of GAPDH is involved in apoptosis induced by a variety of insults in neurons and non-neuronal cells. 16,[18][19][20] However, the role of GAPDH in excitotoxicity-related cell death has not been reported. Therefore, we first performed immunohistochemical staining with a GAPDH-specific antibody to show that GAPDH was accumulated in the nuclei of CGC stimulated with SYM for 8 h and that this process was associated with cell shrinkage ( Figure 5A).…”

Section: Chromatin Immunoprecipitation (Chip) Assaymentioning

confidence: 99%

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Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons

et al. 2004

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Valproic acid (VPA), used to treat bipolar mood disorder and seizures, also inhibits histone deacetylase (HDAC). Here, we found that VPA and other HDAC inhibitors, butyrate and trichostatin A, robustly protected mature cerebellar granule cell cultures from excitotoxicity induced by SYM 2081 ((2S, 4R)-4-methylglutamate), an inhibitor of excitatory amino-acid transporters and an agonist of low-affinity kainate receptors. These neuroprotective effects required protracted treatment and were correlated with enhanced acetylated histone levels, indicating HDAC inhibition. SYM-induced excitotoxicity was blocked by MK-801 ((5R,10S)-( þ )-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate), supporting that the toxicity was largely N-methyl-D-aspartate receptor dependent. SYM excitotoxicity had apoptotic characteristics and was prevented by a caspase inhibitor. SYMinduced apoptosis was associated with a rapid and robust nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a housekeeping gene previously shown to be proapoptotic. VPA pretreatment suppressed SYM 2081-induced GAPDH nuclear accumulation, concurrent with its neuroprotective effects. Chromatin immunoprecipitation (ChIP) revealed that GAPDH is copresent with acetylated histone H3, including Lys9-acetylated histone, and that VPA treatment caused a time-dependent decrease in the levels of nuclear GAPDH with a concomitant increase in acetylated histones in the ChIP complex. Our results strongly suggest that VPA protects neurons from excitotoxicity through inhibition of HDAC activity and that this protective effect may involve suppression of excitotoxicity-induced accumulation of GAPDH protein in the nucleus.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Chromatin Immunoprecipitation (Chip) Assaymentioning

confidence: 99%

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Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons

et al. 2004

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“…In addition to its well-known role in glycolysis, GAPDH contributes to nuclear signaling pathways that initiate apoptotic cascades. 97,98 Translocation of GAPDH from the cytosol to the nucleus occurs in a number of cell systems during apoptosis. 97,98 Moreover, recent work reported a genetic association between the GAPDH locus on chromosome 12 and an elevated risk of late-onset AD, suggesting a possible contribution of GAPDH-mediated neurotoxicity to neurodegeneration.…”

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

confidence: 99%

“…97,98 Translocation of GAPDH from the cytosol to the nucleus occurs in a number of cell systems during apoptosis. 97,98 Moreover, recent work reported a genetic association between the GAPDH locus on chromosome 12 and an elevated risk of late-onset AD, suggesting a possible contribution of GAPDH-mediated neurotoxicity to neurodegeneration. 99 However, the sequence encoding GAPDH lacks a nuclear localization signal, and therefore the molecular pathway to cell death has remained enigmatic.…”

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

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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.

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Recruitment of PCM1 to the Centrosome by the Cooperative Action of DISC1 and BBS4

Kamiya¹,

Tan²,

Kubo³

et al. 2008

Arch Gen Psychiatry

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125

159

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Context A role for the centrosome has been suggested in the pathology of major mental illnesses, especially schizophrenia (SZ). Objectives To show that pericentriolar material-1 protein (PCM1) forms a complex at the centrosome with Disrupted-In-Schizophrenia-1 (DISC1) and Bardet-Biedl syndrome-4 protein (BBS4), which provides a crucial pathway for cortical development associated with the pathology of SZ. To identify mutations in the PCM1 gene in a SZ population. Design Interaction of DISC1, PCM1, and BBS proteins was assessed by immunofluorescent staining and co-immunoprecipitation. Effects of PCM1, DISC1, and BBS on centrosomal functions and corticogenesis in vivo were tested by RNAi. PCM1 gene was examined by sequencing 39 exons and flanking splice sites. Setting and Patients Thirty-two probands with SZ from families that had excess allele sharing among affected individuals at 8p22, and 219 Caucasian controls. Main Outcome Measures Protein interaction and recruitment at the centrosome in cells; neuronal migration in the cerebral cortex; variant discovery in PCM1 in SZ patients. Results PCM1 forms a complex with DISC1 and BBS4 through discrete binding domains in each protein. DISC1 and BBS4 are required for targeting PCM1 and other cargo proteins, such as ninein, to the centrosome in a synergistic manner. In the developing cerebral cortex, suppression of PCM1 leads to neuronal migration defects, which are phenocopied by the suppression of either DISC1 or BBS4, and are exacerbated by the concomitant suppression of both. Furtheremore, a nonsense mutation that segregates with schizophrenia-spectrum psychosis is found in one family. Conclusion Our data further support for the role of centrosomal proteins in cortical development and suggest that perturbation of centrosomal function contributes to the development of mental diseases including SZ.

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Glyceraldehyde-3-phosphate dehydrogenase: Nuclear translocation participates in neuronal and nonneuronal cell death

Cited by 305 publications

References 43 publications

Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons

Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons

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

Recruitment of PCM1 to the Centrosome by the Cooperative Action of DISC1 and BBS4

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