Cryo-EM studies of amyloids in neurodegenerationGroup Leader Page
Abnormal filamentous inclusions of the proteins tau and alpha-synuclein characterise multiple neurodegenerative diseases, which are called tauopathies and synucleinopathies, respectively. Alzheimer's disease is the most common tauopathy; Parkinson's disease the most common synucleinopathy. In close collaboration with the Goedert group in the Neurobiology division at MRC-LMB, we use cryo-EM to study the 3D structures of tau and alpha-synuclein filaments that are extracted from human brains of various diseases (e.g. Fitzpatrick et al, 2017; Schweighauser et al, 2020). We have found that different folds characterise different diseases, and that commonly employed methods to generate amyloid filaments in the laboratory do not replicate the disease-related structures. It is currently unclear what drives the structural specificity of amyloid formation in the different diseases, and hence what is needed to develop more relevant model systems to study these. In this project, which will be jointly supervised with Michel Goedert, the student will explore multiple in vitro and in cellulo amyloid formation systems and use cryo-EM structure determination to verify that the correct 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.
Approximately half of the Scheres group works on algorithm development for cryo-EM image processing in the RELION software. Two years ago, this work culminated in the first atomic resolution reconstruction of a protein by single-particle analysis (Nakane et al, 2020). Although this year's student would preferably work in the experimental, amyloid side of the group, as outlined above, outstanding candidates with a background in numerical data processing and computer programming, possibly including deep-learning approaches, will also be considered for a project on algorithm development.
A.W.P. Fitzpatrick, B. Falcon, S. He, A.G. Murzin, G. Murshudov, H.J. Garringer, R.A. Crowther, B. Ghetti, M. Goedert & S.H.W. Scheres (2017)
Cryo-EM structures of tau filaments from Alzheimer's disease.
Nature 547, 185-190, http://dx.doi.org/doi:10.1038/nature23002
Schweighauser, Y. Shi, A. Tarutani, F. Kametani, A.G. Murzin, B. Ghetti, T. Matsubara, T. Tomita, T. Ando, K. Hasegawa, S. Murayama, M. Yoshida, M. Hasegawa, S.H.W. Scheres & M. Goedert (2020)
Structures of alpha-synuclein filaments from multiple system atrophy.
Nature 585, 464-469, https://doi.org/10.1038/s41586-020-2317-6
Nakane, A. Kotecha, A. Sente, G. McMullan, S. Masiulis, P.M.G.E. Brown, I.T. Grigoras, L. Malinauskaite, T. Malinauskas, J. Miehling, T. Uchanski, L. Yu, D. Karia, E.V. Pechnikova, E. de Jong, J. Keizer, M. Bischoff, J. McCormack, P. Tiemeijer, S.W. Hardwick, D.Y. Chirgadze, G. Murshudov, A.R Aricescu & S.H.W. Scheres (2020)
Single-particle cryo-EM at atomic resolution.
Nature, 587, 152-156, https://doi.org/10.1038/s41586-020-2829-0