The 3D structure of lipidic fibrils of α-synuclein

alpha-synuclein misfolding and aggregation into fibrils is a common feature of alpha-synucleinopathies, such as Parkinson's disease, in which alpha-synuclein fibrils are a characteristic hallmark of neuronal inclusions called Lewy bodies. Studies on the composition of Lewy bodies extracted postmortem from brain tissue of Parkinson's patients revealed that lipids and membranous organelles are also a significant component. Interactions between alpha-synuclein and lipids have been previously identified as relevant for Parkinson's disease pathology, however molecular insights into their interactions have remained elusive. Here we present cryo-electron microscopy structures of six alpha-synuclein fibrils in complex with lipids, revealing specific lipid-fibril interactions. We observe that phospholipids promote an alternative protofilament fold, mediate an unusual arrangement of protofilaments, and fill the central cavities of the fibrils. Together with our previous studies, these structures also indicate a mechanism for fibril-induced lipid extraction, which is likely to be involved in the development of alpha-synucleinopathies. Specifically, one potential mechanism for the cellular toxicity is the disruption of intracellular vesicles mediated by fibrils and oligomers, and therefore the modulation of these interactions may provide a promising strategy for future therapeutic interventions. Interactions between alpha-synuclein fibrils and lipids have been associated with the development of Parkinson's disease. This cryo-EM study reveals structural details of these interactions and suggests a mechanism for fibril-induced lipid extraction.

Automated summary

Misfolding and aggregation of alpha-synuclein into fibrils is a common characteristic of alpha-synucleinopathies such as Parkinson's disease. This study utilizes cryo-electron microscopy to reveal the detailed structure of the interactions between alpha-synuclein fibrils and lipids, providing insights into the mechanism of fibril-induced lipid extraction.