Chemical properties of lipids strongly affect the kinetics of the membrane-induced aggregation of a-synuclein

Intracellular a-synuclein deposits, known as Lewy bodies, have been linked to a range of neurodegenerative disorders, including Parkinson's disease. a-Synuclein binds to synthetic and biological lipids, and this interaction has been shown to play a crucial role for both a-synuclein's native function, including synaptic plasticity, and the initiation of its aggregation. Here, we describe the interplay between the lipid properties and the lipid binding and aggregation propensity of a-synuclein. In particular, we have observed that the binding of a-synuclein to model membranes is much stronger when the latter is in the fluid rather than the gel phase, and that this binding induces a segregation of the lipids into protein-poor and protein-rich populations. In addition, a-synuclein was found to aggregate at detectable rates only when interacting with membranes composed of the most soluble lipids investigated here. Overall, our results show that the chemical properties of lipids determine whether or not the lipids can trigger the aggregation of a-synuclein, thus affecting the balance between functional and aberrant behavior of the protein.