α-Synuclein modifies mutant huntingtin aggregation and neurotoxicity in Drosophila

Gonçalo M. Poças, Joana Branco-Santos, Federico Herrera, Tiago Fleming Outeiro, Pedro M. Domingos

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish
Article numberddu606
Pages (from-to)1898-1907
Number of pages10
JournalHuman molecular genetics
Volume24
Issue number7
DOIs
Publication statusPublished - Apr 2015

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