Abnormal filamentous inclusions characterise many human neurodegenerative diseases, including Alzheimer’s and Parkinson’s. The formation of filaments or their mere presence is believed to result in the propagation of inclusions and neurodegeneration. Our work showed that the intracellular filaments of these diseases are made of either tau or alpha-synuclein.
We and others identified mutations in MAPT, the tau gene, that cause inherited forms of frontotemporal dementia with tau inclusions, establishing a central role for tau assembly. SNCA, the alpha-synuclein gene, is mutated or multiplied in inherited cases of Parkinson’s disease and dementia with Lewy bodies, and alpha-synuclein is the major component of the filamentous lesions of Parkinson’s disease, other Lewy body disorders and multiple system atrophy.
In collaboration with Sjors Scheres, we are using electron cryo-microscopy to determine the structures of pathological amyloid filaments from the brains of patients with tau and alpha-synuclein proteinopathies. We have so far determined the structures of tau filaments from cases of Alzheimer’s disease, chronic traumatic encephalopathy, Pick’s disease and corticobasal degeneration. Distinct structures are found between diseases, but not between individuals with a given disease. They differ from the structures of heparin-induced filaments of recombinant tau.
We also determined the first structures of brain-derived alpha-synuclein filaments, from multiple system atrophy. Unlike tau filaments, which are characterised by a unique protofilament for each disease, four different protofilaments of alpha-synuclein are seen in multiple system atrophy. The presence of associated densities, possibly non-proteinaceous, is characteristic of tau and alpha-synuclein filaments.
- Schweighauser, M., Shi, Y., Tarutani, A., Kametani, F., Murzin, A.G., Ghetti, B., Matsubara, T., Tomita, T., Ando, T., Hasegawa, K., Murayama, S., Yoshida, M., Hasegawa, M., Scheres, S.H.W. and Goedert, M. (2020)
Structures of α-synuclein filaments from multiple system atrophy.
Nature 585: 464-469.
- Scheres, S.H.W., Zhang, W., Falcon, B. and Goedert, M. (2020)
Cryo-EM structures of tau filaments.
Current Opinion in Structural Biology 64: 17-25.
- Zhang, W., Tarutani, A., Newell, K.L., Murzin, A.G., Matsubara, T., Falcon, B., Vidal, R., Garringer, H.J., Shi, Y., Ikeuchi, T., Murayama, S., Ghetti, B., Hasegawa, M., Goedert, M. and Scheres, S.H.W. (2020)
Novel tau filament fold in corticobasal degeneration.
Nature 580: 283-287.
- Falcon, B., Zivanov, J., Zhang, W., Murzin, A.G., Garringer, H.J., Vidal, R., Crowther, R.A., Newell, K.L., Ghetti, B., Goedert, M. and Scheres, S.H.W. (2019)
Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules.
Nature 568: 420-423.
- Falcon, B., Zhang, W., Schweighauser, M., Murzin, A.G., Vidal, R., Garringer, H.J., Ghetti, B., Scheres, S.H.W. and Goedert, M. (2018)
Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold.
Acta Neuropathologica 136: 699-708.
- Falcon, B., Zhang, W., Murzin, A.G., Murshudov, G., Garringer, H.J., Vidal, R., Crowther, R.A., Ghetti, B., Scheres, S.H.W., and Goedert, M. (2018)
Structures of filaments from Pick’s disease reveal a novel tau protein fold.
Nature 561: 137-140.
- Fitzpatrick, A.W.P., Falcon, B., He, S., Murzin, A.G., Murshudov, G., Garringer, H.J., Crowther, R.A., Ghetti, B., Goedert, M. and Scheres, S.H.W. (2017)
Cryo-EM structures of tau filaments from Alzheimer’s disease.
Nature 547: 185-190.
- Goedert, M., Jakes, R. and Spillantini, M.G. (2017)
The Synucleinopathies: Twenty years on.
Journal of Parkinson’s Disease 7: S51-S69.
- Goedert, M., Eisenberg, D.S., and Crowther, R.A. (2017)
Propagation of tau aggregates and neurodegeneration.
Annual Review of Neuroscience 40: 189-210.
- Taxiarchis Katsinelos
- Isabelle Lavenir
- Jennifer Macdonald
- Manuel Schweighauser