Neuroprotection by pharmacologic blockade of the GAPDH death cascade

Hara, Makoto R.; Thomas, Bobby; Cascio, Matthew B.; Bae, Byoung-Il; Hester, Lynda D.; Dawson, Valina L.; Dawson, Ted M.; Sawa, Akira; Snyder, Solomon H.

doi:10.1073/pnas.0511321103

Cited by 224 publications

(212 citation statements)

References 29 publications

Supporting

Mentioning

200

Contrasting

Unclassified

Order By: Relevance

“…Recent studies showed that S-nitrosylation of GAPDH can mediate the translocation of GAPDH-Siah1 protein complex to the nucleus and initiates apoptosis (29,30). Our findings that S-nitrosylation of XIAP can affect its antiapoptotic function further suggest that nitrosative stress can affect the survival of neurons through targeting a number of pathways.…”

Section: Discussionmentioning

confidence: 69%

See 1 more Smart Citation

S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease

Tsang

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

144

112

View full text Add to dashboard Cite

Inhibitors of apoptosis (IAPs) are a family of highly-conserved proteins that regulate cell survival through binding to caspases, the final executioners of apoptosis. X-linked IAP (XIAP) is the most widely expressed IAP and plays an important function in regulating cell survival. XIAP contains 3 baculoviral IAP repeats (BIRs) followed by a RING finger domain at the C terminal. The BIR domains of XIAP possess anticaspase activities, whereas the RING finger domain enables XIAP to function as an E3 ubiquitin ligase in the ubiquitin and proteasomal system. Our previous study showed that parkin, a protein that is important for the survival of dopaminergic neurons in Parkinson's disease (PD), is S-nitrosylated both in vitro and in vivo in PD patients. S-nitrosylation of parkin compromises its ubiquitin E3 ligase activity and its protective function, which suggests that nitrosative stress is an important factor in regulating neuronal survival during the pathogenesis of PD. In this study we show that XIAP is S-nitrosylated in vitro and in vivo in an animal model of PD and in PD patients. Nitric oxide modifies mainly cysteine residues within the BIR domains. In contrast to parkin, S-nitrosylation of XIAP does not affect its E3 ligase activity, but instead directly compromises its anticaspase-3 and antiapoptotic function. Our results confirm that nitrosative stress contributes to PD pathogenesis through the impairment of prosurvival proteins such as parkin and XIAP through different mechanisms, indicating that abnormal S-nitrosylation plays an important role in the process of neurodegeneration.

show abstract

Section: Discussionmentioning

confidence: 69%

“…Apart from impairing neuroprotection proteins, S-nitrosylation is also involved in mediating cell death through GAPDH (28,29). Recent studies showed that S-nitrosylation of GAPDH can mediate the translocation of GAPDH-Siah1 protein complex to the nucleus and initiates apoptosis (29,30).…”

Section: Discussionmentioning

confidence: 99%

S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease

Tsang

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

144

112

View full text Add to dashboard Cite

show abstract

“…R-(-)-deprenyl (Selegiline), which may ameliorate the progression of early stage PD, appears to prevent S-nitrosylation of GAPDH both in cellular and animal models of PD. 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

“…We further explored this relationship using the pharmacologic drug deprenyl, which is a small molecule inhibitor that binds tightly to GAPDH and prevents its S-nitrosylation at Cys152 (23). Heme insertion into iNOS became resistant to NO inhibition in cells given deprenyl (Fig.…”

Section: Cellular Heme Insertion Into Inos Involves Gapdh and Is Regula-mentioning

confidence: 99%

GAPDH regulates cellular heme insertion into inducible nitric oxide synthase

Chakravarti

Aulak

Fox

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

128

146

View full text Add to dashboard Cite

Heme proteins play essential roles in biology, but little is known about heme transport inside mammalian cells or how heme is inserted into soluble proteins. We recently found that nitric oxide (NO) blocks cells from inserting heme into several proteins, including cytochrome P450s, hemoglobin, NO synthases, and catalase. This finding led us to explore the basis for NO inhibition and to identify cytosolic proteins that may be involved, using inducible NO synthase (iNOS) as a model target. Surprisingly, we found that GAPDH plays a key role. GAPDH was associated with iNOS in cells. Pure GAPDH bound tightly to heme or to iNOS in an NO-sensitive manner. GAPDH knockdown inhibited heme insertion into iNOS and a GAPDH mutant with defective heme binding acted as a dominant negative inhibitor of iNOS heme insertion. Exposing cells to NO either from a chemical donor or by iNOS induction caused GAPDH to become S -nitrosylated at Cys152. Expressing a GAPDH C152S mutant in cells or providing a drug to selectively block GAPDH S -nitrosylation both made heme insertion into iNOS resistant to the NO inhibition. We propose that GAPDH delivers heme to iNOS through a process that is regulated by its S -nitrosylation. Our findings may uncover a fundamental step in intracellular heme trafficking, and reveal a mechanism whereby NO can govern the process.

show abstract

Neuroprotection by pharmacologic blockade of the GAPDH death cascade

Cited by 224 publications

References 29 publications

S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease

S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease

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

GAPDH regulates cellular heme insertion into inducible nitric oxide synthase

Contact Info

Product

Resources

About