With Sjors Scheres.

Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are major human synucleinopathies. They are defined by the presence of abundant alpha-synuclein filaments in brain cells. Different brain regions and cells are affected, suggesting the existence of distinct strains of aggregated alpha-synuclein. Nothing is known about the structures of alpha-synuclein filaments from brain.

We have shown that electron cryo-microscopy (cryo-EM) can be used to obtain high-resolution structures of tau filaments from Alzheimer’s and Pick’s disease brains. This work established that specific molecular conformers of aggregated tau define different diseases, without there being significant variation in filament structure between individuals with a given disease.

This project aims to do for alpha-synuclein filaments what we have done previously for tau filaments. We will extract alpha-synuclein filaments from different brain regions of patients with PD, DLB and MSA. They will be obtained from various collaborators and publicly funded Brain Banks in the UK and elsewhere. The achievable resolution of filament structures from a given disease case by cryo-EM is mainly determined by the amounts of filaments that can be extracted from brain. We will therefore screen a large number of brains and use those with the largest number of alpha-synuclein filaments for structure determination. In parallel, we will also use alpha-synuclein filaments from mice transgenic for the human protein for structure determination.

References

Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, Crowther RA, Ghetti B, Goedert M and Scheres SHW (2017)
Cryo-EM structures of tau filaments from Alzheimer’s disease.
Nature, 547, 185-190.

Falcon B, Zhang W, Murzin AG, Murshudov G, Garringer HJ, Vidal R, Crowther RA, Ghetti B, Scheres SHW and Goedert M (2018)
Structures of filaments from Pick’s disease reveal a novel tau protein fold.
Nature, in press.