Neuroprotection by pharmacologic blockade of the GAPDH death cascade

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

doi:10.1073/pnas.0511321103

Neuroprotection by pharmacologic blockade of the GAPDH death cascade

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

192 Scopus citations

Abstract

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) participates in a cell death cascade wherein a variety of stimuli activate nitric oxide (NO) synthases with NO nitrosylating GAPDH, conferring on it the ability to bind to Siah, an E3-ubiquitin-ligase, whose nuclear localization signal enables the GAPDH/Siah protein complex to translocate to the nucleus where degradation of Siah targets elicits cell death. R-(-)-Deprenyl (deprenyl) ameliorates the progression of disability in early Parkinson's disease and also has neuroprotective actions. We show that deprenyl and a related agent, TCH346, in subnanomolar concentrations, prevent S-nitrosylation of GAPDH, the binding of GAPDH to Siah, and nuclear translocation of GAPDH. In mice treated with the dopamine neuronal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), low doses of deprenyl prevent binding of GAPDH and Siah1 in the dopamine-enriched corpus striatum.

Original language	English (US)
Pages (from-to)	3887-3889
Number of pages	3
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	103
Issue number	10
DOIs	https://doi.org/10.1073/pnas.0511321103
State	Published - Mar 7 2006

Keywords

Apoptosis
Nitric oxide
Parkinson's disease
S-nitrosylation
Siah

ASJC Scopus subject areas

General

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10.1073/pnas.0511321103

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title = "Neuroprotection by pharmacologic blockade of the GAPDH death cascade",

abstract = "Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) participates in a cell death cascade wherein a variety of stimuli activate nitric oxide (NO) synthases with NO nitrosylating GAPDH, conferring on it the ability to bind to Siah, an E3-ubiquitin-ligase, whose nuclear localization signal enables the GAPDH/Siah protein complex to translocate to the nucleus where degradation of Siah targets elicits cell death. R-(-)-Deprenyl (deprenyl) ameliorates the progression of disability in early Parkinson's disease and also has neuroprotective actions. We show that deprenyl and a related agent, TCH346, in subnanomolar concentrations, prevent S-nitrosylation of GAPDH, the binding of GAPDH to Siah, and nuclear translocation of GAPDH. In mice treated with the dopamine neuronal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), low doses of deprenyl prevent binding of GAPDH and Siah1 in the dopamine-enriched corpus striatum.",

keywords = "Apoptosis, Nitric oxide, Parkinson's disease, S-nitrosylation, Siah",

author = "Hara, {Makoto R.} and Bobby Thomas and Cascio, {Matthew B.} and Bae, {Byoung Il} and Hester, {Lynda D.} and Dawson, {Valina L.} and Dawson, {Ted M.} and Akira Sawa and Snyder, {Solomon H.}",

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AU - Hara, Makoto R.

AU - Thomas, Bobby

AU - Cascio, Matthew B.

AU - Bae, Byoung Il

AU - Hester, Lynda D.

AU - Dawson, Valina L.

AU - Dawson, Ted M.

AU - Sawa, Akira

AU - Snyder, Solomon H.

PY - 2006/3/7

Y1 - 2006/3/7

N2 - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) participates in a cell death cascade wherein a variety of stimuli activate nitric oxide (NO) synthases with NO nitrosylating GAPDH, conferring on it the ability to bind to Siah, an E3-ubiquitin-ligase, whose nuclear localization signal enables the GAPDH/Siah protein complex to translocate to the nucleus where degradation of Siah targets elicits cell death. R-(-)-Deprenyl (deprenyl) ameliorates the progression of disability in early Parkinson's disease and also has neuroprotective actions. We show that deprenyl and a related agent, TCH346, in subnanomolar concentrations, prevent S-nitrosylation of GAPDH, the binding of GAPDH to Siah, and nuclear translocation of GAPDH. In mice treated with the dopamine neuronal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), low doses of deprenyl prevent binding of GAPDH and Siah1 in the dopamine-enriched corpus striatum.

AB - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) participates in a cell death cascade wherein a variety of stimuli activate nitric oxide (NO) synthases with NO nitrosylating GAPDH, conferring on it the ability to bind to Siah, an E3-ubiquitin-ligase, whose nuclear localization signal enables the GAPDH/Siah protein complex to translocate to the nucleus where degradation of Siah targets elicits cell death. R-(-)-Deprenyl (deprenyl) ameliorates the progression of disability in early Parkinson's disease and also has neuroprotective actions. We show that deprenyl and a related agent, TCH346, in subnanomolar concentrations, prevent S-nitrosylation of GAPDH, the binding of GAPDH to Siah, and nuclear translocation of GAPDH. In mice treated with the dopamine neuronal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), low doses of deprenyl prevent binding of GAPDH and Siah1 in the dopamine-enriched corpus striatum.

KW - Apoptosis

KW - Nitric oxide

KW - Parkinson's disease

KW - S-nitrosylation

KW - Siah

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Neuroprotection by pharmacologic blockade of the GAPDH death cascade

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