The protein α-syn aggregates are constituents of Lewy bodies, a histological hallmark of the synuceinopathies Parkinson's disease, Lewy body dementia and multiple system atrophy.

Elucidating the forms α-syn molecules adopt upon staking within aggregates is key for the design of ligands targeting those aggregates. Such ligands could attach along or at the ends of the resulting fibrils and affect their surface properties or their ability to elongate and thus limit the pathological processes involved in synucleinopathies.

Partner CNRS within a collaborative study with experts in Cryo-Electron microscopy recently determined a new structure for α-syn fibrils, down to an atomic level. Those fibrils, when injected into rodent models, cause the development of symptoms characteristic of Parkinson's disease.

The team obtained their results by combining biochemical to biostructural approaches, specifically solid-state nuclear magnetic resonance and cryo-electron microscopy. Cryo-electron microscopy, abbreviated "cryo-EM", is a method for the preparation of biological samples used in transmission electron microscopy. Developed in the early 1980s, cryo-EM has the advantage of reducing irradiation damages caused by the electron beam. It employs a technique called vitrification to very rapidly freeze samples and thus protect their morphology and molecular structure.

These results, published in eLife,  bring new insight into understanding the mechanisms and factors involved in aggregates formation in vitro and may furthermore enable the development of ligands targeting α-syn fibrils. Such ligands could be used to differentiate pathogenic aggregates from their normal form of their protein constituent or to prevent aggregates from growing by blocking their ends.

The electron micrograph of fibrillar α-syn protein allows the reconstruction of the fibrils at an atomic-level in three dimensions. The fibrils appear to be made of two protofibrils (blue and green) winding around one another. The tip of the fibril is shown on the right. The image reveals the molecular fold of α-syn within the protofibrils in their fibrillar state. α-syn molecules have the same conformation in the two protofibrils constituting the fibrils. The protofibrils are linked by a pair of symmetric salt bridges running along the fibril axis.

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