Neuronal protection by a variant of GAPDH pseudogene P44 in AD

Sara O. Mason, Christopher S. Theisen, Norbert W. Seidler

Department of Biochemistry, Kansas City University of Medicine and Biosciences, Kansas City, USA.

DOI: 10.4236/aad.2012.13011                

Abstract

GAPDH is a conserved enzyme that binds diverse proteins, such as Siah during apoptotic nuclear translocation. There is one somatic GAPDH gene, but over 60 pseudogenes, the expression of which is nebulous. A single nucleotide polymorphism (SNP) in the GAPDHP44 pseudogene exhibits a beneficial allele in AD. The objective of this study was to examine the P44 gene and to propose a mechanism for the putative protein and its impact on AD. We examined the sequences in the putative coding region of the human GAPDHP44 gene and the upstream genetic elements usinga bioinformatics approach. We compared the amino acid sequences of the putative gene product with that of the parent GAPDH protein. There is a TATA box 24 nt upstream from, and a Kozak sequence at, putative transcription and translation start sites, respecttively. The upstream region also has sequences (7 - 16 nt) paralogous to those in parent gene introns; one shows homology to a known enhancer element. The resulting protein would contain 139 aa due to a stop codon, roughly the same size as the dinucleotide domain (151 aa) of the parent protein. The SNP is in a region (residues 80 - 120) that binds to the protein GOSPEL. We propose that the beneficial SNP may cause a glutamine to glutamate substitution. NMDA-stmulated neurons undergo GAPDH nitrosylation, Siah translocation, but can be rescued by GOSPEL binding to GAPDH. Our model suggests that the putative P44 protein may regulate GAPDH-GO-SPEL interaction and the beneficial SNPmay ameliorate AD.

Keywords

GAPDH, Alzheimer’s Disease; Pseudogene; GAPDHP44; SNP; Apoptotic Nuclear Translocation; Siah; GOSPEL

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Seidler, N.W. (2012) Compartmentation of GAPDH. Advances in Experimental Medicine and Biology, 985, 61- 101. doi:10.1007/978-94-007-4716-6_3
[2]	Hara, M.R., et al. (2006) Neuroprotection by pharmacologic blockade of the GAPDH death cascade. Proceedings of National Academy of Sciences of the USA, 103, 3887-3889. doi:10.1073/pnas.0511321103
[3]	Seidler, N.W. (2012) Basic biology of GAPDH. Advances in Experimental Medicine and Biology, 985, 1-36. doi:10.1007/978-94-007-4716-6_1
[4]	Seidler, N.W. (2012) Multiple binding partners. Advances in Experimental Medicine and Biology, 985, 249-267. doi:10.1007/978-94-007-4716-6_8
[5]	Sunaga, K., Takahashi, H., Chuang, D.M. and Ishitani, R. (1995) Glyceraldehyde-3-phosphate dehydrogenase is overexpressed during apoptotic death of neuronal cultures and is recognized by a monoclonal antibody against amyloid plaques from Alzheimer’s brain. Neuroscience Letters, 200, 133-136. doi:10.1016/0304-3940(95)12098-O
[6]	Sultana, R., Boyd-Kimball, D. and Cai, J., et al. (2007) Proteomics analysis of the Alzheimer’s disease hippocampal proteome. Journal of Alzheimer’s disease, 11, 153-164.
[7]	Seidler, N.W. (2012) Target for diverse chemical modifications. Advances in Experimental Medicine and Biology, 985, 179-206. doi:10.1007/978-94-007-4716-6_6
[8]	Mazzola, J.L. and Sirover, M.A. (2001) Reduction of glyceraldehyde-3-phosphate dehydrogenase activity in Alzheimer’s disease and in Huntington’s disease fibroblasts. Journal of Neurochemistry, 76, 442-449. doi:10.1046/j.1471-4159.2001.00033.x
[9]	Ishitani, R. and Chuang, D.M. (1996) Glyceraldehyde- 3-phosphate dehydrogenase antisense oligodeoxynucleotides protect against cytosine arabinonucleoside-induced apoptosis in cultured cerebellar neurons. Proceedings of National Academy of Sciences of the USA, 93, 9937-9941. doi:10.1073/pnas.93.18.9937
[10]	Ishitani, R., Sunaga, K., Hirano, A., Saunders, P., Katsube, N. and Chuang, D.M. (1996) Evidence that glyceraldehyde-3-phosphate dehydrogenase is involved in age-induced apoptosis in mature cerebellar neurons in culture. Journal of Neurochemistry, 66, 928-935. doi:10.1046/j.1471-4159.1996.66030928.x
[11]	Ishitani, R., Tanaka, M., Sunaga, K., Katsube, N. and Chuang, D.M. (1998) Nuclear localization of overexpressed glyceraldehyde-3-phosphate dehydrogenase in cultured cerebellar neurons undergoing apoptosis. MolPharmacol, 53, 701-707.
[12]	Li, Y., et al. (2004) Association of late-onset Alzheimer’s disease with genetic variation in multiple members of the GAPD gene family. Proceedings of National Academy of Sciences of the USA, 101, 15688-15693. doi:10.1073/pnas.0403535101
[13]	Lee, J.H., et al. (2008) Further examination of the candidate genes in chromosome 12p13 locus for late-onset Alzheimer disease. Neurogenetics, 9, 127-138. doi:10.1007/s10048-008-0122-8
[14]	Lin, P.I., et al. (2006) Exploring the association of glyceraldehyde-3-phosphate dehydrogenase gene and Alzheimer disease. Neurology, 67, 64-68. doi:10.1212/01.wnl.0000223438.90113.4e
[15]	Bertram, L., McQueen, M.B., Mullin, K., Blacker, D. and Tanzi, R.E. (2007) Systematic meta-analyses of Alzheimer disease genetic association studies: The AlzGene database. Nature Genetics, 39, 17-23. doi:10.1038/ng1934
[16]	Seidler, N.W. (2012) Functional diversity. Advances in Experimental Medicine and Biology, 985, 103-147. doi:10.1007/978-94-007-4716-6_4
[17]	Kozak, M. (1986) Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes. Cell, 44, 283-292. doi:10.1016/0092-8674(86)90762-2
[18]	Kozak, M. (1992) Regulation of translation in eukaryotic systems. Annual Reviews: Cell and Developmental Biology, 8, 197-225. doi:10.1146/annurev.cb.08.110192.001213
[19]	Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K. and Walter, P. (2002) Molecular biology of the cell. 4th Edition, Garland Science, New York.
[20]	Drabkin, H.J. and RajBhandary, U.L. (1998) Initiation of protein synthesis in mammalian cells with codons other than AUG and amino acids other than methionine. Molecular and Cellular Biology, 18, 5140-5147.
[21]	Theisen, C.S., Seidler, K.A. and Seidler, N.W. (2012) Computational criteria for the disablement of human GAPDH pseudogenes. In: Arabnia, H.R. and Tran, Q.-N., Eds., Proceedings of the 2012 International Conference on Bioinformatics and Computational Biology, CSREA Press, Las Vegas, 158-165.
[22]	Montalbano, A.J., Theisen, C.S., Fibuch, E.E. and Seidler, N.W. (2012) Isoflurane enhances the moonlighting activity of GAPDH: Implications for GABAA receptor trafficking. ISRN Anesthesiology, 2012, Article ID: 970795.
[23]	Kaneda, M., Takeuchi, K., Inoue, K. and Umeda, M. (1997) Localization of the phosphatidylserine-binding site of glyceraldehyde-3-phosphate dehydrogenase responseble for membrane fusion. Journal of Biochemistry, 122, 1233-1240. doi:10.1093/oxfordjournals.jbchem.a021886
[24]	Alvarez-Dominguez, C., et al. (2008) Characterization of a Listeria monocytogenes protein interfering with Rab5a. Traffic, 9, 325-337. doi:10.1111/j.1600-0854.2007.00683.x
[25]	Marino, S.M. and Gladyshev, V.N. (2010) Cysteine function governs its conservation and degeneration and restricts its utilization on protein surfaces. Journal of Molecular Biology, 404, 902-916. doi:10.1016/j.jmb.2010.09.027
[26]	O’Donoghue, P., Sheppard, K., Nureki, O. and Söll, D. (2011) Rational design of an evolutionary precursor of glutaminyl-tRNAsynthetase. Proceedings of National Academy of Sciences of the USA, 108, 20485-20490. doi:10.1073/pnas.1117294108
[27]	Wilcox, M. and Nirenberg, M. (1968) Transfer RNA as a cofactor coupling amino acid synthesis with that of protein. Proceedings of National Academy of Sciences of the USA, 61, 229-236. doi:10.1073/pnas.61.1.229
[28]	Hara, M.R., et al. (2005) S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nature Cell Biology, 7, 665-674. doi:10.1038/ncb1268
[29]	Sen, N., et al. (2008) Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. Nature Cell Biology, 10, 866-873. doi:10.1038/ncb1747
[30]	Morris, J.C. and Price, J.L. (2001) Pathologic correlates of nondemented aging, mild cognitive impairment, and early-stage Alzheimer’s disease. Journal of Molecular Neuroscience, 17, 101-118. doi:10.1385/JMN:17:2:101