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.2006 Mar 7;103(10):3887-9.
doi: 10.1073/pnas.0511321103. Epub 2006 Feb 27.

Neuroprotection by pharmacologic blockade of the GAPDH death cascade

Affiliations

Neuroprotection by pharmacologic blockade of the GAPDH death cascade

Makoto R Hara et al. Proc Natl Acad Sci U S A..

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.

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Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.
Fig. 1.
Deprenyl and TCH346 inhibitS-nitrosylation of GAPDH. (a) Chemical structure of deprenyl and TCH346 (i.e., CGP3466). (b) Deprenyl (DEP) inhibitsS-nitrosylation of GAPDH (SNO GAPDH). RAW264.7 cells were untreated, treated with deprenyl (1 nM), treated with LPS and IFN-γ (LPS-IFN), or treated with LPS-IFN and deprenyl for 24 h. (c) TCH346 inhibitsS-nitrosylation of GAPDH. RAW264.7 cells were untreated, treated with LPS, or treated with LPS and TCH346 for 24 h.
Fig. 2.
Fig. 2.
Deprenyl and TCH346 inhibit the binding of GAPDH and Siah1. (a) Deprenyl (DEP) inhibits the binding of GAPDH and Siah1in vitro. GAPDH was preincubated with deprenyl at 0 nM (n = 5), 0.01 nM (n = 2), 0.1 nM (n = 3), or 1 nM (n = 4). GST-Siah1 was added, and binding was assessed by GSH-agarose pull down followed by Western blotting. The graph represents densitometry analysis of Western blotting (error bars indicate SEM; ∗,P < 0.0001; ∗∗,P < 0.00005). (b) Deprenyl inhibits the binding of GAPDH and Siah1. RAW264.7 cells were untreated, treated with deprenyl (1 nM), treated with LPS and IFN-γ (LPS-IFN), or treated with LPS-IFN and deprenyl for 24 h. Cell lysates were immunoprecipitated with α -Siah1 antibody. (c andd) RAW264.7 cells were treated the same as inb. (c) TCH346 inhibits the binding of GAPDH and Siah1. (d) Deprenyl and TCH346 inhibit the nuclear translocation of GAPDH. Nuclear fractions were analyzed by Western blotting.
Fig. 3.
Fig. 3.
Deprenyl prevents apoptotic cell death in cerebellar granule neurons. Etoposide (100 μM) was added to primary cerebellar granule neuron cultures 4–5 days after plating. Cytotoxicity was monitored 20 h after the addition of etoposide. Deprenyl (DEP) exerts cytoprotective effects (P < 0.01), whereas tranylcypromine, a monoamine oxidase inhibitor that lacks GAPDH binding properties, is ineffective. The extent of cell death parallels increased levels of Siah1 and nuclear GAPDH.
Fig. 4.
Fig. 4.
Deprenyl inhibits the binding of GAPDH and Siah1 in MPTP-treated mice. (a)S-nitrosylation of GAPDH (SNO GAPDH) in MPTP-treated mouse brain. Mice were treated as described inMaterials and Methods, and the brain lysate was subjected to the biotin switch assay. (b) Deprenyl (DEP) inhibits the binding of GAPDH and Siah1 in MPTP treated mouse striatum. Mice were treated as described inMaterials and Methods. Striatum region was dissected, and its lysate was used for coimmunoprecipitation assay.
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References

    1. Kofman O. S. N. Engl. J. Med. 1993;328:1715. - PubMed
    1. The Parkinson Study Group. N. Engl. J. Med. 1989;321:1364–1371. - PubMed
    1. Correspondences to The Parkinson Study Group. N. Engl. J. Med. 1990;322:1526–1528.
    1. The Parkinson Study Group. N. Engl. J. Med. 1993;328:176–183. - PubMed
    1. Paterson I. A., Barber A. J., Gelowitz D. L., Voll C. Neurosci. Biobehav. Rev. 1997;21:181–186. - PubMed

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