RESEARCH HIGHLIGHT - Structures of alpha-synuclein filaments from multiple system atrophy

Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are synucleinopathies. They are characterised by the presence of abundant filamentous inclusions of alpha-synuclein (α-syn) in nerve cells and glial cells, in the form of Lewy bodies and Papp-Lantos bodies. The relevance of inclusion formation was established when gene dosage and missense mutations in SNCA, the α-syn gene, were shown to cause inherited forms of PD and DLB, with abundant Lewy pathology. In diseases with Lewy pathology, α-syn inclusions are found mostly in nerve cells, whereas they predominate in glial cells in MSA. Several indirect lines of evidence have suggested that the inclusions in diseases with Lewy pathology and those in MSA are different conformers of assembled α-syn.

Direct evidence requires knowledge of the high-resolution structures of α-syn filaments from the brains of individuals with PD, DLB and MSA. In this Nature publication, we determined the first near-atomic structures of α-syn filaments from human brain with MSA using electron cryo-microscopy (cryo-EM).Two types of filament (Type I and Type II) were identified, which differed in structure from those of assembled recombinant wild-type and mutant α-syn. Each filament type comprised two asymmetric protofilaments, with a non-proteinaceous, probably hydrophilic, density at protofilament interfaces. Different ratios of Type I and Type II filaments were present in distinct brain regions of the same cases and in the same brain regions of different cases. 

α-syn filaments from the brains of individuals with Parkinson’s disease and dementia with Lewy bodies are thinner and less twisted than those from individuals with multiple system atrophy, making it more difficult to determine their high-resolution structures. So far, by using two-dimensional class averaging, we have shown that the structures of α-syn filaments from dementia with Lewy bodies are probably different from those of multiple system atrophy.

Filamentous α-syn pathology of MSA.

This project receives funding from the Innovative Medicines Initiative 2 Joint Undertaking ( under grant agreement No 116060. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

This work is supported by the Swiss State Secretariat for Education‚ Research and Innovation (SERI) under contract number 17.00038.

The opinions expressed and arguments employed herein do not necessarily reflect the official views of these funding bodies.

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