Glycation, an age-dependent posttranslational protein modification, has been reported in several neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. This non-enzymatic reaction between reducing sugars and free amino-groups from proteins, interferes with the aggregation process of proteins such as amyloid-beta and alpha-synuclein. As methylglyoxal (MGO) is the most important glycation agent, here we interrogated whether MGO glycation could also play a role in huntingtin (HTT) biology. Using a versatile yeast model, we observed that glycation increased the aggregation of a HTT exon 1 fragment (HTT72Q or HTT103Q). We also observed that glycation promoted aggregation and toxicity in human neuroglioma cells expressing HTT103Q. Notably, MGO treatment of HTT93Q transgenic flies potentiates neuronal loss in a dose-dependent manner. In total, this study suggests that glycation might contribute to huntingtin dysfunction and may constitute a novel target for therapeutic intervention in HD.
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