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Sci Rep. 2016 Nov 18;6:36798. doi: 10.1038/srep36798.

Glycation potentiates neurodegeneration in models of Huntington's disease.

Author information

1
CEDOC, Chronic Diseases Research Centre, NOVA Medical School | Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisboa, Portugal.
2
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
3
Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom.
4
Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Estação Agronomica Nacional, Av. da República, Oeiras 2780-157, Portugal.
5
Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University Medical Center Göttingen, Waldweg 33, 37073 Göttingen, Germany.
6
Max Planck Institute for Experimental Medicine, Göttingen, Germany.

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.

PMID:
27857176
PMCID:
PMC5114697
DOI:
10.1038/srep36798
[Indexed for MEDLINE]
Free PMC Article

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