title: Glycation potentiates neurodegeneration in models of Huntington's disease.
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.
authors.affiliation: 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.|Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Hugo
authors.initials: H
authors.lastname: Vicente Miranda
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Marcos António
authors.initials: MA
authors.lastname: Gomes
authors.affiliation: Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom.|Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Estação Agronomica Nacional, Av. da República, Oeiras 2780-157, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Branco-Santos
authors.affiliation: Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom.
authors.forename: Carlo
authors.initials: C
authors.lastname: Breda
authors.affiliation: 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.
authors.forename: Diana F
authors.initials: DF
authors.lastname: Lázaro
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Luísa Vaqueiro
authors.initials: LV
authors.lastname: Lopes
authors.affiliation: Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Estação Agronomica Nacional, Av. da República, Oeiras 2780-157, Portugal.
authors.forename: Federico
authors.initials: F
authors.lastname: Herrera
authors.affiliation: Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom.
authors.forename: Flaviano
authors.initials: F
authors.lastname: Giorgini
authors.affiliation: 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.|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.|Max Planck Institute for Experimental Medicine, Göttingen, Germany.
authors.forename: Tiago Fleming
authors.initials: TF
authors.lastname: Outeiro
mesh_terms: D000818:Animals; D001343:Autophagy; D002460:Cell Line; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics / Q000378:metabolism*; D005091:Exons; D005260:Female; D020868:Gene Silencing; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein / Q000378:metabolism*; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae; D016896:Treatment Outcome
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D049452:Green Fluorescent Proteins