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.

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