Abnormal filamentous inclusions of the proteins amyloid-β, tau and α-synuclein define multiple neurodegenerative diseases, which are called β-amyloidoses, tauopathies and synucleinopathies, respectively. Alzheimer’s disease is the most common β-amyloidosis and tauopathy, whereas Parkinson’s disease is the most common synucleinopathy.
In close collaboration with the Scheres Group from the Division of Structural Studies of the LMB, we are using cryo-EM to study the 3D structures of amyloid-β 42, tau and α-synuclein filaments that were extracted from the brains of humans with a variety of neurodegenerative diseases (e.g. Schweighauser et al., 2020; Shi et al., 2021; Yang et al., 2022). We have found that different folds characterise different diseases and that commonly used methods to generate amyloid filaments in the laboratory do not replicate disease-related structures from the human brain. It is currently not clear what drives the structural specificity of amyloid formation in the different diseases, and hence what is needed to develop more relevant model systems.
In this project, which will be jointly supervised by Sjors Scheres and Michel Goedert, the student will explore multiple model systems (in test tubes, cells and mice) and use cryo-EM structure determination to verify that the correct structures have formed. These ongoing studies have already generated some success (Lövestam et al., 2022), but much more work remains to be done. In the end, we hope to understand the molecular determinants of amyloid formation and develop experimental systems that replicate what is going wrong in human brains.
References
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 & Goedert M. (2020)
Structures of α-synuclein filaments from multiple system atrophy.
Nature 585, 464-469.
Shi Y, Zhang W, Yang Y, Murzin AG, Falcon B, Kotecha A, van Beers M, Tarutani A, Kametani F, Garringer HJ, Vidal R, Hallinan GI, Lashley T, Saito Y, Murayama S, Yoshida M, Tanaka H, Kakita A, Ikeuchi T, Robinson AC, Mann DMA, Kovacs GG, Revesz T, Ghetti B, Hasegawa M, Goedert M & Scheres SHW. (2021)
Structure-based classification of tauopathies.
Nature 598, 359-363.
Yang Y, Arseni D, Zhang W, Huang M, Lövestam S, Schweighauser M, Kotecha A, Murzin AG, Peak-Chew SY, Macdonald J, Lavenir I, Garringer HJ, Gelpi E, Newell KL, Kovacs GG, Vidal R, Ghetti B, Ryskeldi-Falcon B, Scheres SHW & Goedert M. (2022)
Cryo-EM structures of amyloid-β 42 filaments from human brains.
Science 375, 167-172.
Lövestam S, Koh FA, van Knippenberg B, Kotecha A, Murzin AG, Goedert M & Scheres SHW. (2022)
Assembly of recombinant tau into filaments identical to those of Alzheimer’s disease and chronic traumatic encephalopathy.
eLife 11, e76494.