Significance: The deposition of α-synuclein as insoluble amyloid fibrils and the spreading of such species in the brain are two hallmarks of Parkinson disease. It is therefore of great importance to understand in detail the process of aggregation of this protein. We show by a series of in vitro measurements that amyloid fibrils of α-synuclein can grow under a wide range of solution conditions but that they can multiply rapidly only under a much more select set of solution conditions, mimicking those in endosomes and other organelles. The quantitative characterization of α-synuclein aggregation described here provides new insights into the microscopic mechanisms underlying α-synuclein aggregation in the context of Parkinson disease.

Significance: Proteinaceous deposits composed primarily of amyloid fibrils of α-synuclein are a hallmark of a range of neurological disorders including Parkinson’s disease. Mutations of the gene encoding α-synuclein have been associated with familial variants of Parkinson’s disease and lead to early- and late-onset forms of the disease. Using a combination of experimental and theoretical approaches specifically designed for the study of α-synuclein, we report that the mutations dramatically affect the rate of lipid-induced fibril production and surface-catalyzed fibril amplification processes. Such a systematic study provides new insights into the influence that single-amino acid replacements in α-synuclein can have on the two steps of α-synuclein aggregation that are likely to be crucial for disease: the initial formation of aggregates and their proliferation.

Significance: Parkinson’s disease is the second most prevalent neurodegenerative disorder and is characterized by the presence in the brains of patients of proteinaceous deposits whose main component is α-synuclein. This protein interacts with membranes as part of its biological function, but this interaction also modulates its kinetics of aggregation. Here, we show that, despite the fact that α-synuclein binds to different types of membranes, it only forms amyloid fibrils in the presence of the most soluble lipids investigated here. This finding is of particular significance because it shows that modifications of the chemical properties of lipids, such as those associated with oxidation and ageing, could be a key determinant of the switch between functional and deleterious interactions between α-synuclein and membranes.