title: α-Synuclein modifies mutant huntingtin aggregation and neurotoxicity in Drosophila.
abstract: Protein misfolding and aggregation is a major hallmark of neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Until recently, the consensus was that each aggregation-prone protein was characteristic of each disorder [α-synuclein (α-syn)/PD, mutant huntingtin (Htt)/HD, Tau and amyloid beta peptide/AD]. However, growing evidence indicates that aggregation-prone proteins can actually co-aggregate and modify each other's behavior and toxicity, suggesting that this process may also contribute to the overlap in clinical symptoms across different diseases. Here, we show that α-syn and mutant Htt co-aggregate in vivo when co-expressed in Drosophila and produce a synergistic age-dependent increase in neurotoxicity associated to a decline in motor function and life span. Altogether, our results suggest that the co-existence of α-syn and Htt in the same neuronal cells worsens aggregation-related neuropathologies and accelerates disease progression.
authors.affiliation: Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. da República, Oeiras 2780-157, Portugal.
authors.forename: Gonçalo M
authors.initials: GM
authors.lastname: Poças
authors.affiliation: Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. da República, Oeiras 2780-157, Portugal, Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisboa 1649-029, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Branco-Santos
authors.affiliation: Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. da República, Oeiras 2780-157, Portugal, Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisboa 1649-029, Portugal.
authors.forename: Federico
authors.initials: F
authors.lastname: Herrera
authors.affiliation: Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisboa 1649-029, Portugal Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Goettingen, Waldweg 33, Goettingen 37073, Germany.
authors.forename: Tiago Fleming
authors.initials: TF
authors.lastname: Outeiro
authors.affiliation: Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. da República, Oeiras 2780-157, Portugal, domingp@itqb.unl.pt.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Domingos
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D066329:Protein Aggregates; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D066329:Protein Aggregates; D051844:alpha-Synuclein