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Glycation potentiates neurodegeneration in models of Huntington's disease

Lookup NU author(s): Professor Tiago Outeiro

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2016 The Author(s).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.


Publication metadata

Author(s): Vicente Miranda H, Gomes MA, Branco-Santos J, Breda C, Lazaro DF, Lopes LV, Herrera F, Giorgini F, Outeiro TF

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2016

Volume: 6

Online publication date: 18/11/2016

Acceptance date: 21/10/2016

Date deposited: 20/12/2017

ISSN (print): 2045-2322

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/srep36798

DOI: 10.1038/srep36798


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