Chemical synthesis of site-selective advanced glycation end products in α-synuclein and its fragments

The risk of developing Parkinson’s disease (PD) is elevated in people with type 2 diabetes, but the precise molecular pathways underlying this connection are still unclear. One hypothesis is that glycation, a non-enzymatic family of reactions between glycating agents, such as reducing sugars or reactive dicarbonyls, and specific amino acids, such as lysines and arginines, may alter proteostasis and trigger pathological alterations. Glycation of alpha-synuclein (aSyn), a central player in PD pathology, causes profound changes in the aggregation process of aSyn. Methylglyoxal (MGO), a strong glycating agent, induces the formation of pathological inclusions enriched in phosphorylated aSyn on serine 129 (pS129). In addition, we found that neuroinflammatory responses are enhanced by MGO-mediated aSyn glycation. Using novel polyclonal antibodies developed towards specific MGO-glycated aSyn residues, we confirmed the occurrence of glycated aSyn bothin vitroas well as in animal and in human brain tissue. In total, our findings shed light into the interplay between glycation, PD, and type 2 diabetes, potentially paving the way for the development of novel therapeutic strategies targeting these intertwined conditions.

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Elucidating the Antiglycation Effect of Creatine on Methylglyoxal-Induced Carbonyl Stress In Vitro

Koike,

Mitsuhashi,

Kishida

et al. 2024

IJMS

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Advanced glycation end products (AGEs) with multiple structures are formed at the sites where carbonyl groups of reducing sugars bind to free amino groups of proteins through the Maillard reaction. In recent years, it has been highlighted that the accumulation of AGEs, which are generated when carbonyl compounds produced in the process of sugar metabolism react with proteins, is involved in various diseases. Creatine is a biocomponent that is homeostatically present throughout the body and is known to react nonenzymatically with α-dicarbonyl compounds. This study evaluated the antiglycation potential of creatine against methylglyoxal (MGO), a glucose metabolite that induces carbonyl stress with formation of AGEs in vitro. Further, to elucidate the mechanism of the cytoprotective action of creatine, its effect on the accumulation of carbonyl proteins in the cells and the MGO-induced cellular damage were investigated using neuroblastoma cells. The results revealed that creatine significantly inhibits protein carbonylation by directly reacting with MGO, and creatine added to the culture medium suppressed MGO-derived carbonylation of intracellular proteins and exerted a protective effect on MGO-induced cytotoxicity. These findings suggest that endogenous and supplemented creatine may contribute to the attenuation of carbonyl stress in vivo.

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Chemical synthesis of site-selective advanced glycation end products in α-synuclein and its fragments

Abstract: Advanced glycation end products (AGEs) arise from the Maillard reaction between dicarbonyls and proteins, nucleic acids, or specific lipids. Notably, AGEs are linked to aging and implicated in various disorders,...

Cited by 3 publications

References 57 publications

Non-enzymatic posttranslational protein modifications in protein aggregation and neurodegenerative diseases

Non-enzymatic posttranslational protein modifications in protein aggregation and neurodegenerative diseases

Glycation of alpha-synuclein enhances aggregation and neuroinflammatory responses

Elucidating the Antiglycation Effect of Creatine on Methylglyoxal-Induced Carbonyl Stress In Vitro

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