The review analyses data on specific features of aggregation of
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and possible role of this
enzyme in the development of
neurodegenerative diseases. Different post-translational modifications of the
enzyme are considered: oxidation, nitrosylation, and S-glutathionylation of the active site sulfhydryl groups, as well as phosphorylation, glycation and homocysteinylation of other
amino acid residues. Modification of the sulfhydryl groups of the
enzyme inhibits the enzymatic activity of GAPDH, resulting in slowdown of glycolysis, and may lead to the dissociation of the cofactor
NAD from the active site of the
enzyme. The resulting apo-GAPDH (without
NAD) is less stable and prone to dissociation, denaturation, and subsequent aggregation. These processes could play a crucial role in the translocation of GAPDH subunits from the cytoplasm into the nucleus, which is linked to the induction of apoptosis. Phosphorylation and glycation of GAPDH are presumably involved in the regulation of
protein-
protein interactions and intracellular localization of the
enzyme. Besides, glycation by dicarbonyl compounds and
aldehydes may directly inhibit glycolysis. Homocysteinylation of GAPDH may stabilize aggregates of the
enzyme by additional
disulfide bonding. All types of post-translational modifications affect aggregation of GAPDH. A special attention is given to the role of chaperones in the amyloidogenic transformation of
proteins and to confirmation of the hypothesis on blocking of the chaperones by misfolded
protein forms. The denatured GAPDH forms were shown to interact directly with
amyloidogenic proteins (
alpha-synuclein and
amyloid-beta peptide) and to play a crucial role in blocking of chaperone system.