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Title: Glycation potentiates neurodegeneration in models of Huntington's disease
Authors: Vicente Miranda, H.
Gomes, M. A.
Branco-Santos, Joana
Breda, Carlo
Lázaro, D. F.
Lopes, L. V.
Herrera, F
Giorgini, Flaviano
Outeiro, T. F.
First Published: 18-Nov-2016
Publisher: Nature Publishing Group
Citation: Scientific Reports, 2016, 6:36798
Abstract: 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.
DOI Link: 10.1038/srep36798
ISSN: 2045-2322
eISSN: 2045-2322
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit
Appears in Collections:Published Articles, Dept. of Genetics

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