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B08 Glycation Modulates Huntingtin Aggregation And Toxicity
  1. HV Miranda1,
  2. MA Gomes1,
  3. J Branco dos Santos1,2,
  4. F Giorgini2,
  5. TF Outeiro1,3
  1. 1Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
  2. 2Department of Genetics, University of Leicester, Leicester LE1 7RH, UK
  3. 3Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University Medical Center Göttingen, Waldweg 33, 37073 Göttingen, Germany

Abstract

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.

KeyWords
  • Glycation
  • Huntingtin
  • Aggregation

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