Abnormal filamentous inclusions of the proteins amyloid-beta, tau and alpha-synuclein characterise multiple human neurodegenerative diseases, which are called beta-amyloidoses, tauopathies and synucleinopathies, respectively. Alzheimer's disease is the most common beta-amyloidosis and tauopathy; Parkinson's disease is the most common synucleinopathy. In close collaboration, the Scheres and Goedert groups use cryo-EM to study the 3D structures of amyloid-beta, tau and alpha-synuclein filaments that are extracted from the brains of patients with various diseases (e.g. Fitzpatrick et al, 2017; Yang et al, 2022a,b). We have found that a specific fold characterises each disease and that commonly employed methods to generate amyloid filaments in the laboratory do not replicate the disease-related structures (Scheres et al, 2023). It is currently unclear what drives the structural specificity of amyloid formation in the different diseases, and hence what is needed is to develop more relevant model systems to study these. In this project, which will be jointly supervised by Sjors and Michel, the student will explore a number of experimental amyloid formation systems and use cryo-EM structure determination to verify that the correct folds are formed. Knowledge gained will lead to a better understanding of the molecular determinants of amyloid formation, whereas the development of laboratory-based model systems for amyloid formation will lead to invaluable tools for gaining insights of the molecular mechanisms that underlie these diseases.

References

Fitzpatrick, A.W.P., Falcon, B., He, S., Murzin, A.G., Murshudov, G., Garringer, H.J., Crowther, R.A., Ghetti, B., Goedert, M., Scheres, S.H.W. (2017)
Cryo-EM structures of tau filaments from Alzheimer's disease
Nature 547(7662): 185-190

Yang, Y., Arseni, D., Zhang, W., Huang, M., Lövestam, S., Schweighauser, M., Kotecha, A., Murzin, A.G., Peak-Chew, S.Y., Macdonald, J., Lavenir, I., Garringer, H.J., Gelpi, E., Newell, K.L., Kovacs, G.G., Vidal, R., Ghetti, B., Ryskeldi-Falcon, B., Scheres, S.H.W., Goedert, M. (2022)
Cryo-EM structures of amyloid-β 42 filaments from human brains
Science 375(6577): 167-172

Yang, Y., Shi, Y., Schweighauser, M., Zhang, X., Kotecha, A., Murzin, A.G., Garringer, H.J., Cullinane, P.W., Saito, Y., Foroud, T., Warner, T.T., Hasegawa, K., Vidal, R., Murayama, S., Revesz, T., Ghetti, B., Hasegawa, M., Lashley, T., Scheres, S.H.W., Goedert, M. (2022)
Structures of α-synuclein filaments from human brains with Lewy pathology
Nature 610(7933): 791-795

Scheres, S.H.W., Ryskeldi-Falcon, B., Goedert, M. (2023)
Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids
Nature 621(7980): 701-710