Molecular mechanisms of neurodegeneration
Abnormal filamentous inclusions characterise many human neurodegenerative diseases, including Parkinson’s and Alzheimer’s. The formation of filaments or their mere presence is believed to result in the propagation of inclusions and in neurodegeneration. Our work showed that the intracellular filaments of these diseases are made of either alpha-synuclein or tau protein.
SNCA, the alpha-synuclein gene, is mutated or multiplied in rare inherited cases of Parkinson’s disease and dementia with Lewy bodies, and alpha-synuclein is the major component of the filamentous lesions in all cases of Parkinson’s disease, other Lewy body disorders and multiple system atrophy.
We and others identified mutations in MAPT, the tau gene, that cause rare inherited forms of frontotemporal dementia with tau inclusions, establishing a central role for tau assembly. In collaboration with Sjors Scheres and others, we used electron cryo-microscopy to show that the paired helical and straight filaments of sporadic Alzheimer’s disease are ultrastructural polymorphs that differ in their inter-protofilament packing. They share two identical C-shaped protofilaments with a combined cross-β/β-helix structure; each protofilament consists of V306-F378 of tau (in the numbering of the 441 amino acid isoform). In sporadic Pick’s disease, a form of frontotemporal dementia, narrow Pick filaments are made of a single protofilament with an elongated cross-β structure that extends from K254 to F378 of tau (lacking V275-S305). Wide Pick filaments consist of two narrow filaments joined at their distal tips. These findings establish that assembled tau adopts distinct folds in different neurodegenerative diseases.
We now aim to determine additional high-resolution structures of disease filaments. Ultimately, we wish to understand the pathological pathways that lead from monomeric alpha-synuclein and tau to their ordered assembly and to neurodegeneration.
- 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.
- Brelstaff, J., Tolkovsky, A.M., Ghetti, B., Goedert, M., and Spillantini, M.G. (2018)
Living neurons with tau filaments aberrantly expose phosphatidylserine and are phagocytosed by microglia.
Cell Reports 24: 1939-1948.
- Mund, T., Masuda-Suzukake, M., Goedert, M., and Pelham, H.R. (2018)
Ubiquitination of alpha-synuclein filaments by Nedd4 ligases.
PLoS ONE 13: e200763.
- Kundel, F., Hong, L., Falcon, B., McEwan, W.A., Michaels, T.C.T., Meisl, G., Esteras, N., Abramov, A.Y., Knowles, T.J.P., Goedert, M., and Klenerman, D. (2018)
Measurement of tau filament fragmentation provides insights into prion-like spreading.
ACS Chemical Neuroscience 9: 1276-1282.
- Falcon, B., Noad, J., McMahon, H., Randow, F., and Goedert, M. (2018)
Galectin-8-mediated selective autophagy protects against seeded tau aggregation.
Journal of Biological Chemistry 293: 2438-2451.
- 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.
- McEwan, W.A., Falcon, B., Vaysburd, M., Clift, D., Oblak, A.L., Ghetti, B., Goedert, M., and James, L.C. (2017)
Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation.
Proceedings of the National Academy of Sciences (USA) 114: 574-579.
- 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.
- Ben Falcon
- Juan Fan
- Isabelle Lavenir
- Jennifer Macdonald
- Manuel Schweighauser
- Yang Shi