Assembly of a small number of proteins into abnormal filamentous amyloid inclusions characterizes many human neurodegenerative diseases, including Alzheimer’s and Parkinson’s. Most cases of disease are sporadic, but some are inherited in a dominant manner. Close links exist between filament assembly and the causes of inherited disease. By extrapolation, inclusion formation may underlie all cases of disease. It is therefore important to understand the mechanisms that lead to filament assembly in human brain. Tau and alpha-synuclein are among the most commonly assembled proteins in neurodegenerative diseases.  Over the past four years, in a close collaboration with the Scheres group in the Structural Studies Division, we used electron cryo-microscopy (cryo-EM) to study the structures of tau and alpha-synuclein filaments extracted from diseased human brains (e.g. Fitzpatrick et al., 2017; Schweighauser et al., 2020; Scheres et al., 2020). So far, we have found that distinct conformers of filamentous tau define different tauopathies and that multiple conformers of assembled alpha-synuclein probably define Lewy body diseases and multiple system atrophy. Differences in filament folds are between diseases, not between individuals with a given disease. We have also found that commonly used methods to generate amyloids in vitro do not replicate the human disease folds. It is currently not known what drives the structural specificity of amyloid formation in different diseases, and hence what is needed to generate more relevant model systems. In this project, which will be supervised jointly with Sjors Scheres, the student will explore multiple in vitro and in cellulo amyloid formation systems, together with cryo-EM structure determination. This work may lead to the production and characterization of authentic animal models of human disease.

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.

Schweighauser M, Shi Y, Tarutani A, Kametani F, Murzin AG, Ghetti B, Matsubara T, Tomita T, Ando T, Hasegawa K, Murayama S, Yoshida M, Hasegawa M, Scheres SHW and Goedert M (2020)
Structures of alpha-synuclein filaments from multiple system atrophy.
Nature 585, 464-469.

Scheres SHW, Zhang W, Falcon B and Goedert M (2020)
Cryo-EM structures of tau filaments.
Current Opinion in Structural Biology 64, 17-25.