Oxidatively Modified Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) and Alzheimer's Disease: Many Pathways to Neurodegeneration

Abstract

Recently, the oxidoreductase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), has become a subject of interest as more and more studies reveal a surfeit of diverse GAPDH functions, extending beyond traditional aerobic metabolism of glucose. As a result of multiple isoforms and cellular locales, GAPDH is able to come in contact with a variety of small molecules, proteins, membranes, etc., that play important roles in normal and pathologic cell function. Specifically, GAPDH has been shown to interact with neurodegenerative disease-associated proteins, including the amyloid-beta protein precursor (AbetaPP). Studies from our laboratory have shown significant inhibition of GAPDH dehydrogenase activity in Alzheimer's disease (AD) brain due to oxidative modification. Although oxidative stress and damage is a common phenomenon in the AD brain, it would seem that inhibition of glycolytic enzyme activity is merely one avenue in which AD pathology affects neuronal cell development and survival, as oxidative modification can also impart a toxic gain-of-function to many proteins, including GAPDH. In this review, we examine the many functions of GAPDH with respect to AD brain; in particular, the apparent role(s) of GAPDH in AD-related apoptotic cell death is emphasized.

Glyceraldehyde-3-phosphate Dehydrogenase (GAPDH) Phosphorylation by Protein Kinase Cδ (PKCδ) Inhibits Mitochondria Elimination by Lysosomal-like Structures following Ischemia and Reoxygenation-induced Injury

“…GAPDH was also reported to be modified under oxidative stress conditions. Specifically, a cysteine residue in the active site of GAPDH was oxidized to cysteic acid, which makes this enzyme inactive (47,48). Although the precise mechanism by which GAPDH is translocated to mitochondria has not yet been determined, oxidative stress in I/R potentially regulates the onset of GAPDH and PKC␦-mediated mitophagy.…”

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

“…It has also been well documented that glyceraldehyde-3-phosphate dehydrogenase (GAPDH), an enzyme that catalyzes the sixth step of glycolysis, possesses a cysteine in its active site, which can be oxidized by reactive oxygen and nitrogen species . This oxidative modification is able to inhibit its dehydrogenase activity, not only affecting the glycolytic metabolism, but also promoting apoptosis, which has important implications in neurodegenerative disorders such as Alzheimer's disease (AD) (Butterfield et al, 2010). As it has been reviewed in (Brandes et al, 2009), there are other metabolic enzymes that can be modified by thiol:disulphide exchange, such as creatine kinase, glycogen synthase or protein phosphatase-I.…”

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

“…Further, MG binds to Cys, Lys, and His residues by Michael addition at a faster kinetic rate than does HNE. In addition, GAPDH is known to affect APP and Tau (71). Consequently, this multifunctional protein could have important biochemical, clinical, and pathological sequelae of relevance to AD (71).…”

“…GAPDH is known for its functional involvement in glycolysis and, consequently, in energy production; therefore, this nitrated protein has altered activity with consequent decreased glucose metabolism (71). In addition, inhibition of GADPH can lead to accumulation of trioses, with subsequent nonenzymatic conversion to methyl glyoxal (MG), a highly reactive alpha-ketoaldehyde that readily oxidizes proteins, lipids, and other cellular components, leading to further cytotoxicity (172).…”

“…As noted, there are three forms of NOS: neuronal (nNOS or Type I), inducible (iNOS or Type II), and endothelial (eNOS or Type III). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) acts as an NO sensor (71,183). Nitric oxide is permeable to the plasma membrane and can bind to guanyl cyclase (204).…”