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A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity

2017; National Academy of Sciences; Volume: 114; Issue: 6 Linguagem: Inglês

10.1073/pnas.1610586114

1091-6490

Michele Perni, Céline Galvagnion, Alexander S. Maltsev, Georg Meisl, Martin Müller, Pavan K. Challa, Julius B. Kirkegaard, Patrick Flagmeier, Samuel I. A. Cohen, Roberta Cascella, Serene W. Chen, Ryan Limbocker, Pietro Sormanni, Gabriella T. Heller, Francesco A. Aprile, Nunilo Cremades, Cristina Cecchi, Fabrizio Chiti, Ellen A. A. Nollen, Tuomas P. J. Knowles, Michele Vendruscolo, Ad Bax, Michael Zasloff, Christopher M. Dobson,

Alzheimer's disease research and treatments

Significance Parkinson’s disease is characterized by the presence in brain tissues of aberrant aggregates primarily formed by the protein α-synuclein. It has been difficult, however, to identify compounds capable of preventing the formation of such deposits because of the complexity of the aggregation process of α-synuclein. By exploiting recently developed highly quantitative in vitro assays, we identify a compound, squalamine, that blocks α-synuclein aggregation, and characterize its mode of action. Our results show that squalamine, by competing with α-synuclein for binding lipid membranes, specifically inhibits the initiation of the aggregation process of α-synuclein and abolishes the toxicity of α-synuclein oligomers in neuronal cells and in an animal model of Parkinson’s disease.