Glycation, glycolysis, and neurodegenerative diseases: Is there any connection?

Abstract

This review considers the interrelation between different types of protein glycation, glycolysis, and the development of amyloid neurodegenerative diseases. The primary focus is on the role of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase in changing the concentration of carbonyl compounds - first and foremost, glyceraldehyde-3-phosphate and methylglyoxal. It has been suggested that various modifications of the enzyme - from the oxidation of the sulfhydryl groups of the active site to glycation with sugars - can lead to its inactivation, which causes a direct increase in glyceraldehyde-3-phosphate concentration and an indirect increase in the content of other aldehydes. This "primary inactivation" of glyceraldehyde-3-phosphate dehydrogenase promotes its glycation with aldehydes, including its own substrate, and a further irreversible decrease in its activity. Such a cycle can lead to numerous consequences - from the induction of apoptosis, which is activated by modified forms of the enzyme, to glycation of amyloidogenic proteins by glycolytic aldehydes. Of particular importance during the inhibition of glyceraldehyde-3-phosphate dehydrogenase is an increase in the content of the glycating compound methylglyoxal, which is much more active than reducing sugars (glucose, fructose, and others). In addition, methylglyoxal is formed by two pathways - in the cascade of reactions during glycation and from glycolytic aldehydes. The ability of methylglyoxal to glycate proteins makes it the main participant in this protein modification. We consider the effect of glycation on the pathological transformation of amyloidogenic proteins and peptides - β-amyloid peptide, α-synuclein, and prions. Our primary focus is on the glycation of monomeric forms of these proteins with methylglyoxal, although most works are dedicated to the analysis of the presence of "advanced glycation end products" in the already formed aggregates and fibrils of amyloid proteins. In our opinion, the modification of aggregates and fibrils is secondary in nature and does not play an important role in the development of neurodegenerative diseases. The glycation of amyloid proteins with carbonyl compounds can be one of the triggers of their transformation into toxic forms. The possible role of glycation of amyloidogenic proteins in the prevention of their modification by ubiquitin and the SUMO proteins due to a disruption of their degradation is separately considered.

Redox Signaling and Advanced Glycation Endproducts (AGEs) in Diet-Related Diseases

“…Considering the relevance of proinflammatory and prooxidant pathways in the pathogenesis of age-related diseases, AGEs are involved in relevant illnesses such as diabetes [59][60][61], insulin resistance, cardiovascular diseases [62,63], chronic renal failure [64], and neurological disorders [65,66].…”

Glycolysis-Derived Compounds From Astrocytes That Modulate Synaptic Communication

“…The main source of MG synthesis is from aldehydes, which are intermediates of the glycolysis pathway, such as glyceraldehyde 3-phosphate and dihydroxyacetone-phosphate (see Figures 1, 3). At physiological or pathological conditions, MG is produced through spontaneous dephosphorylation of dihydroxyacetone-phosphate (Angeloni et al, 2014; Muronetz et al, 2017). Coffee, alcoholic beverages, cigarette smoke and food are all exogenous sources of MG (Nemet et al, 2006; Angeloni et al, 2014).…”

Maillard reaction and aging: can bacteria shed light on the link?

“…The Maillard reaction contributes also to the pathological transformations of amyloidogenic proteins and peptides including b-amyloid peptide, a-synuclein, and prions associated with neurodegenerative diseases such as Alzheimer's, Parkinson's and prion disorders [55,56]. Parkinson's disease (PD) affects 1-2% of the population aged over 65 years and nearly 4% in those aged above 85 years [57].…”

“…The LBs are composed of cytoplasmic a-synuclein (a-syn) aggregates that displace other cellular components. The aggregation of a-syn is promoted by oxidative and carbonyl stress [56,60] and results in the formation of toxic LBs inclusions and insoluble fibrils as well that disrupt the organization of brain areas responsible for motor control. The interaction between AGEs and their cognate receptors contributes to the generation of a prooxidant tissue environment that appears a significant driver of PD [61].…”