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Glycation potentiates neurodegeneration in models of Huntington's disease

journal contribution
posted on 21.11.2016, 14:51 by H. Vicente Miranda, M. A. Gomes, Joana Branco-Santos, Carlo Breda, D. F. Lázaro, L. V. Lopes, F Herrera, Flaviano Giorgini, T. F. Outeiro
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.

Funding

We thank Professor Rui Moreira and Dr. Susana Lucas for MGO purification. Authors were supported by: HVM (Fundação para a Ciência e Tecnologia (FCT), Portugal SFRH/BPD/64702/2009 and SFRH/BPD/109347/2015); JBS (SFRH/BD/85275/2012); FH (SFRH/BPD/63530/2009 and IF/00094/2013); TFO (EMBO Installation Grant; Marie Curie IRG, Neurofold). TFO is supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB). FG is supported by grants from the Medical Research Council (MRC) and the CHDI Foundation, Inc.

History

Citation

Scientific Reports, 2016, 6:36798

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Department of Genetics

Version

VoR (Version of Record)

Published in

Scientific Reports

Publisher

Nature Publishing Group

issn

2045-2322

eissn

2045-2322

Acceptance date

21/10/2016

Available date

21/11/2016

Publisher version

http://www.nature.com/articles/srep36798

Language

en