Glycotoxins: Dietary and Metabolic Origins; Possible Amelioration of Neurotoxicity by Carnosine, with Special Reference to Parkinson’s Disease

Abstract

There is a strong association between neurodegeneration and protein glycation; possible origins of neurotoxic glycated protein, also called glycotoxins, include (i) diet (i.e., proteins cooked at high temperatures), (ii) protein glycation in the gut, and (iii) intracellular reaction of proteins with deleterious aldehydes, especially methylglyoxal (MG). It is likely that excessive glycolysis provokes increased generation of dihydroxyacetone phosphate which decomposes into MG due to activity-induced deamidation of certain asparagine residues in the glycolytic enzyme triose-phosphate isomerase (TPI). It is suggested that, following hyperglycemia, erythrocytes (i) possibly participate in MG distribution throughout the body and (ii) could provide a source of glycated alpha-synuclein which also accumulates in PD brains as Lewy bodies. The dipeptide carnosine, recently shown to be present in erythrocytes, could help to protect against MG reactivity by scavenging the reactive bicarbonyl, especially if glyoxalase activity is insufficient, as often occurs during aging. By reacting with MG, carnosine may also prevent generation of the neurotoxin 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (ADTIQ), which accumulates in PD and diabetic brains. It is suggested that carnosine’s therapeutic potential could be explored via nasal administration in order to avoid the effects of serum carnosinase. The possibility that some glycated proteins (e.g., alpha-synuclein) could possess prion-like properties is also considered.

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Hipkiss, A.R. Glycotoxins: Dietary and Metabolic Origins; Possible Amelioration of Neurotoxicity by Carnosine, with Special Reference to Parkinson’s Disease. Neurotox Res 34, 164–172 (2018). https://doi.org/10.1007/s12640-018-9867-5

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Keywords

  • Glycation
  • Methylglyoxal
  • Triose-phosphate isomerase
  • Carnosine
  • Erythrocytes
  • Glycolysis
  • Diet
  • Prion
  • Alpha-synuclein