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Hum Mol Genet. 2015 Apr 1;24(7):1898-907. doi: 10.1093/hmg/ddu606. Epub 2014 Dec 1.

α-Synuclein modifies mutant huntingtin aggregation and neurotoxicity in Drosophila.

Author information

1
Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. da República, Oeiras 2780-157, Portugal.
2
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.
3
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.
4
Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. da República, Oeiras 2780-157, Portugal, domingp@itqb.unl.pt.

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.

PMID:
25452431
PMCID:
PMC4355023
DOI:
10.1093/hmg/ddu606
[Indexed for MEDLINE]
Free PMC Article

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