Glycation potentiates neurodegeneration in models of Huntington’s disease

• Published in: Scientific reports 2016-11, Vol.6 (1), p.36798-36798, Article 36798
• Main Authors: Vicente Miranda, Hugo, Gomes, Marcos António, Branco-Santos, Joana, Breda, Carlo, Lázaro, Diana F., Lopes, Luísa Vaqueiro, Herrera, Federico, Giorgini, Flaviano, Outeiro, Tiago Fleming
• Format: Article
• Language: English
• Subjects: 13/109; 631/337/458; 631/378/340; 631/378/87; 64/24; 692/699/375; 82/29; 82/51; Age; Alzheimer's disease; Animals; Autophagy; Cell culture; Cell Line; Disease Models, Animal; Drosophila - genetics; Drosophila - metabolism; Eclosion; Exons; Female; Gene Silencing; Glycosylation; Green Fluorescent Proteins - metabolism; Humanities and Social Sciences; Humans; Huntingtin; Huntingtin Protein - metabolism; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington's disease; Huntingtons disease; Male; Movement disorders; multidisciplinary; Mutation; Nerve Tissue Proteins - metabolism; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - metabolism; Neurons - metabolism; Nuclear Proteins - metabolism; Parkinson's disease; Phagocytosis; Saccharomyces cerevisiae; Science; Toxicity; Treatment Outcome; Yeasts
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep36798

Protein glycation is an age-dependent posttranslational modification associated with several neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. By modifying amino-groups, glycation interferes with folding of proteins, increasing their aggregation potential. Here, we studied the effect of pharmacological and genetic manipulation of glycation on huntingtin (HTT), the causative protein in Huntington’s disease (HD). We observed that glycation increased the aggregation of mutant HTT exon 1 fragments associated with HD (HTT72Q and HTT103Q) in yeast and mammalian cell models. We found that glycation impairs HTT clearance thereby promoting its intracellular accumulation and aggregation. Interestingly, under these conditions autophagy increased and the levels of mutant HTT released to the culture medium decreased. Furthermore, increased glycation enhanced HTT toxicity in human cells and neurodegeneration in fruit flies, impairing eclosion and decreasing life span. Overall, our study provides evidence that glycation modulates HTT exon-1 aggregation and toxicity, and suggests it may constitute a novel target for therapeutic intervention in HD.