Advances in Alzheimer's Disease
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 using a 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, respectively. 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-stimulated 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 SNP may ameliorate AD.
GAPDH, Alzheimer’s Disease, Pseudogene, GAPDHP44, SNP, Apoptotic Nuclear Translocation, Siah, GOSPEL
Mason SO, Theisen CS, Seidler NW. Neuronal Protection by a Variant of GAPDH Pseudogene P44 in AD. Advances in Alzheimer's Disease. 2012; 1(3). doi: 10.4236/aad.2012.13011.