Alpha-synuclein aggregates form insoluble fibrils that are constituents of Lewy bodies, a histological hallmark of certain pathologies such as Parkinson's disease, Lewy body dementia and multiple system atrophy, all of which are grouped as a family of pathologies called synucleinopathies.
Elucidating the forms alpha-synuclein 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 to affect their surface properties or their ability to elongate and thus limit the pathological processes involved in synucleinopathies.
As part of an international partnership, researchers from the Neurodegenerative Diseases Laboratory (LMN/MIRCen) recently determined a new structure for alpha-synuclein fibrils, down to the 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 damage caused by the electron beam. It employs a technique called vitrification to very rapidly freeze samples and thus protect their morphology and molecular structure.
The work by the international team brings a better understanding of the mechanisms and factors involved in aggregates formation in vitro and may furthermore enable the development of ligands targeting alpha-synuclein fibrils. Such ligands could be used to differentiate pathogenic aggregates from their normal protein counterparts or to prevent aggregates from growing by blocking their extremities.
The multidisciplinary collaborative work opens new avenues for the development of diagnostic or therapeutic compounds for Parkinson's disease.
Fibrillar structure of alpha-synuclein proteins under the electron microscope. The atomic-level three-dimensional reconstruction shows that the fibrils are 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 alpha-synuclein within the protofibrils in their fibrillar position and the orientations of the amino acid side chains. Alpha-synuclein molecules have the same conformation in the two protofibrils constituting the fibril. The protofibrils are linked by a pair of symmetric salt bridges between a lysine (K45) and a glutamic acid (E57) stacked along the fibril axis. (Credit picture : Luc Bousset)