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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\u2019s 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.<\/jats:p>","DOI":"10.1038\/srep36798","type":"journal-article","created":{"date-parts":[[2016,11,18]],"date-time":"2016-11-18T11:03:32Z","timestamp":1479467012000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Glycation potentiates neurodegeneration in models of Huntington\u2019s disease"],"prefix":"10.1038","volume":"6","author":[{"given":"Hugo","family":"Vicente Miranda","sequence":"first","affiliation":[]},{"given":"Marcos Ant\u00f3nio","family":"Gomes","sequence":"additional","affiliation":[]},{"given":"Joana","family":"Branco-Santos","sequence":"additional","affiliation":[]},{"given":"Carlo","family":"Breda","sequence":"additional","affiliation":[]},{"given":"Diana F.","family":"L\u00e1zaro","sequence":"additional","affiliation":[]},{"given":"Lu\u00edsa Vaqueiro","family":"Lopes","sequence":"additional","affiliation":[]},{"given":"Federico","family":"Herrera","sequence":"additional","affiliation":[]},{"given":"Flaviano","family":"Giorgini","sequence":"additional","affiliation":[]},{"given":"Tiago Fleming","family":"Outeiro","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2016,11,18]]},"reference":[{"key":"BFsrep36798_CR1","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1016\/0092-8674(93)90585-E","volume":"72","author":"ME MacDonald","year":"1993","unstructured":"MacDonald, M. 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