Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Alzheimer's disease

Kadmiri, Nadia El; Moutawakil, Bouchra El; Nadifi, Sellama; Tadevosyan, Artavazd; Hachem, A.; Soukri, Abdelaziz

doi:10.1016/j.patbio.2014.08.002

Cited by 45 publications

(30 citation statements)

References 52 publications

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“…In mammals, GAPDH participates in membrane fusion, microtubule bundling, nuclear RNA export, DNA replication and repair and apoptosis, and it is in these non-glycolytic roles that mammalian GAPDH has been associated with various diseases including cancer (Zhang et al, 2015), viral pathogenesis (Allonso et al, 2015), Huntington's disease (Hwang et al, 2015; Mikhaylova et al, 2016), Parkinson's disease (Liu et al, 2015) and Alzheimer's disease (El Kadmiri et al, 2014). Bacterial GAPDH enzymes have also shown a wide functional repertoire (Henderson and Martin, 2014).…”

Section: Introductionmentioning

confidence: 99%

Crystal Structure of Glyceraldehyde-3-Phosphate Dehydrogenase from the Gram-Positive Bacterial Pathogen A. vaginae, an Immunoevasive Factor that Interacts with the Human C5a Anaphylatoxin

Querol-García¹,

Fernández

Marín

et al. 2017

Front. Microbiol.

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The Gram-positive anaerobic human pathogenic bacterium Atopobium vaginae causes most diagnosed cases of bacterial vaginosis as well as opportunistic infections in immunocompromised patients. In addition to its well-established role in carbohydrate metabolism, D-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from Streptococcus pyogenes and S. pneumoniae have been reported to act as extracellular virulence factors during streptococcal infections. Here, we report the crystal structure of GAPDH from A. vaginae (AvGAPDH) at 2.19 Å resolution. The refined model has a crystallographic Rfree of 22.6%. AvGAPDH is a homotetramer wherein each subunit is bound to a nicotinamide adenine dinucleotide (NAD+) molecule. The AvGAPDH enzyme fulfills essential glycolytic as well as moonlight (non-glycolytic) functions, both of which might be targets of chemotherapeutic intervention. We report that AvGAPDH interacts in vitro with the human C5a anaphylatoxin and inhibits C5a-specific granulocyte chemotaxis, thereby suggesting the participation of AvGAPDH in complement-targeted immunoevasion in a context of infection. The availability of high-quality structures of AvGAPDH and other homologous virulence factors from Gram-positive pathogens is critical for drug discovery programs. In this study, sequence and structural differences between AvGAPDH and related bacterial and eukaryotic GAPDH enzymes are reported in an effort to understand how to subvert the immunoevasive properties of GAPDH and evaluate the potential of AvGAPDH as a druggable target.

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Section: Introductionmentioning

confidence: 99%

Crystal Structure of Glyceraldehyde-3-Phosphate Dehydrogenase from the Gram-Positive Bacterial Pathogen A. vaginae, an Immunoevasive Factor that Interacts with the Human C5a Anaphylatoxin

Querol-García¹,

Fernández

Marín

et al. 2017

Front. Microbiol.

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“…Changes in brain metabolism could also be underlying human specific neurodegenerative diseases correlated with metabolic failures, such as Alzheimer’s disease [Bufill et al, 2013]. GAPDH is know to provide glycolytic energy in fast axonal transport during vesicle trafficking [Zala et al, 2013] and is implicated in Alzheimer’s disease, among other neurodegenerative diseases [El Kadmiri et al, 2014].…”

Section: Discussionmentioning

confidence: 99%

Modern human alleles differentially regulate gene expression across brain regions: implications for brain evolution

Andirkó

Boeckx

2019

Preprint

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8The high-quality sequence of the genomes of our extinct relatives, Ne-9 anderthals and Denisovans, became recently public. At the same time, 10 we have seen the emergence of big databases of modern human genetic 11 variation. However, linking human genetic variation, neuronal phenotypes 12 and, eventually, behaviour, is only possible if we understand how variation 13 and genetic regulation interact. We used two publicly available datasets, 14 the GTEX cis-eQTL database (v7) and a catalog of high-frequency Homo 15 Sapiens specific alleles relative to the Neanderthals and Denisovan se-16 quences, to understand how high-frequency Homo Sapiens derived alleles 17 affect gene expression regulation. The resulting dataset shows that genes 18 associated with brain development are affected by Homo sapiens-specific 19 eQTL in brain areas key in human evolution such as the cerebellum. We 20 also show that some of these eQTL overlap significantly with putative 21 regions of positive selection relative to archaic humans [Peyrégne et al., 22 2017]. Additionally, we tested whether any of the variants are associated 23 with clinical conditions in modern human populations. These findings can 24 inform future experimental work and enrich current venues of research of 25 the Homo Sapiens brain evolution, such as the relationship between clini-26 cal and evolutionary research and the recent expansion of the cerebellum 27 in Homo Sapiens [Gunz et al., 2010].28 Keywords-Human evolution, eQTL, brain evolution 29 and Boeckx, 2019]). 75 Our results show differential regulation by derived cis-eQTLs in key brain 76 areas and circuits that are claimed to have changed significantly during the 77 emergence of Homo sapiens, such as the cerebellum and olfactory signalling 78 pathway [Bastir et al., 2011]. We also found genetic regulation of cellular pro-79 cesses that can potentially impact neurodevelopment and disease, such as fo-80 late one-carbon metabolism, aerobic glycolysis regulation, cell-cell adhesion and 81 regulation of cytoskeleton dynamics. Some of these processes, such as aerobic 82 glycolysis, have already been discussed in other studies in the context of human 83 evolution and human-specific diseases such as Alzheimer's Disease [Bufill et al., 84 2011]. While we limited the scope of our study to brain tissue, we found as 85 well eQTLs associated with neural crest cell development and the craniofacial 86 complex. This is of special interest, as the Homo sapiens face has a distinct re-87 tracted profile compared to that of archaic humans [Lacruz et al., 2019]. Some 88 of the genes that affect brain development might exert an influence in adjacent 89 tissues [Boeckx, 2017]. 90 Since the eQTLs affect genes previously identified as under selective sweep in 91 modern humans relative to archaic humans, we tested whether the eQTLs affect 92 128 2015]. In this case, the effect of an eQTL is understood as the relative gene 129 expression difference between the minor, ancestral allele and the high-frequency 130 derived allele. As shown ...

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“…GAPDH has been implicated in various human diseases; increased nuclear localization of GAPDH correlates with increased neuronal apoptosis in Parkinson disease (61), Huntington disease (62), and Alzheimer disease (63), and increased glycolytic activity correlates with cancer cell survival (64). GAPDH is also an attractive target for drugs against protozoan parasites, whose bloodstream forms depend solely on glycolysis for energy (65).…”

Section: Discussionmentioning

confidence: 99%

Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) Protein-Protein Interaction Inhibitor Reveals a Non-catalytic Role for GAPDH Oligomerization in Cell Death

Qvit

Joshi

Cunningham

et al. 2016

Journal of Biological Chemistry

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Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), an important glycolytic enzyme, has a non-catalytic (thus a noncanonical) role in inducing mitochondrial elimination under oxidative stress. We recently demonstrated that phosphorylation of GAPDH by ␦ protein kinase C (␦PKC) inhibits this GAPDH-dependent mitochondrial elimination. ␦PKC phosphorylation of GAPDH correlates with increased cell injury following oxidative stress, suggesting that inhibiting GAPDH phosphorylation should decrease cell injury. Using rational design, we identified pseudo-GAPDH (GAPDH) peptide, an inhibitor of ␦PKC-mediated GAPDH phosphorylation that does not inhibit the phosphorylation of other ␦PKC substrates. Unexpectedly, GAPDH decreased mitochondrial elimination and increased cardiac damage in an animal model of heart attack. Either treatment with GAPDH or direct phosphorylation of GAPDH by ␦PKC decreased GAPDH tetramerization, which corresponded to reduced GAPDH glycolytic activity in vitro and ex vivo. Taken together, our study identified the potential mechanism by which oxidative stress inhibits the protective GAPDHmediated elimination of damaged mitochondria. Our study also identified a pharmacological tool, GAPDH peptide, with interesting properties. GAPDH peptide is an inhibitor of the interaction between ␦PKC and GAPDH and of the resulting phosphorylation of GAPDH by ␦PKC. GAPDH peptide is also an inhibitor of GAPDH oligomerization and thus an inhibitor of GAPDH glycolytic activity. Finally, we found that GAPDH peptide is an inhibitor of the elimination of damaged mitochondria. We discuss how this unique property of increasing cell damage following oxidative stress suggests a potential use for GAPDH peptide-based therapy.Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a glycolytic enzyme that catalyzes the conversion of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate. We previously found that in addition to its role as a glycolytic enzyme, GAPDH is also involved in mitochondrial elimination by mitophagy (1). GAPDH binds to damaged mitochondria, and its phosphorylation by ␦ protein kinase C (␦PKC) under oxidative stress inhibits the removal of the damaged mitochondria through mitophagy (1). We set out to determine whether ␦PKC-mediated GAPDH phosphorylation alone is sufficient to mediate cell death following oxidative stress, using Langendorff, an ex vivo model of heart attack.We first designed a novel inhibitor that selectively inhibits GAPDH phosphorylation without affecting the phosphorylation of other ␦PKC substrates. To this end, we relied on the rationale that, similar to many other protein kinases, ␦PKC contains a highly conserved catalytic domain and a regulatory domain that keeps the enzyme in an inactive conformation. This inactive conformation is stabilized by several intramolecular auto-inhibitory interactions (2). The first intramolecular interaction identified was the one mediated by the pseudosubstrate site located at the N terminus of the kinase, which mimics the phospho-acceptor sequence in PKC substrate...

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Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Alzheimer's disease

Cited by 45 publications

References 52 publications

Crystal Structure of Glyceraldehyde-3-Phosphate Dehydrogenase from the Gram-Positive Bacterial Pathogen A. vaginae, an Immunoevasive Factor that Interacts with the Human C5a Anaphylatoxin

Crystal Structure of Glyceraldehyde-3-Phosphate Dehydrogenase from the Gram-Positive Bacterial Pathogen A. vaginae, an Immunoevasive Factor that Interacts with the Human C5a Anaphylatoxin

Modern human alleles differentially regulate gene expression across brain regions: implications for brain evolution

Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) Protein-Protein Interaction Inhibitor Reveals a Non-catalytic Role for GAPDH Oligomerization in Cell Death

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