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A new structure for aggregated alpha-synuclein has been determined at the atomic level using cryo-electron microscopy. The work, lead by a team from MIRCen's Neurodegenerative Diseases Laboratory, was published in the journal
eLife. The determination of this previously undescribed structure opens new doors for the development of ligands specifically targeting alpha-synuclein aggregates in Parkinson's disease.
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.
Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy I eLife
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