Molecular mechanisms of neurodegeneration
The ordered assembly of tau protein and alpha-synuclein into abnormal filamentous inclusions underlies 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 in neurodegeneration.
Our work has shown that the intraneuronal filaments of these diseases are made of either tau or alpha-synuclein.
In Alzheimer’s disease, hyperphosphorylated tau forms paired helical and straight filaments, the cores of which consist of V306-F378 (in the numbering of the 441 amino acid tau isoform). The identification of mutations in MAPT, the tau gene, in inherited forms of frontotemporal dementia with abundant tau filaments, has established the central role of tau assembly for neurodegeneration and dementia.
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 in all cases of Parkinson’s disease, other Lewy body disorders and multiple system atrophy.
Our current work is aimed at understanding the pathological pathways that lead from monomeric tau and alpha-synuclein to their ordered assembly into filaments.
- 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
bioRxiv, doi: 10.1101/302216.
- 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.
- Ben Falcon
- Juan Fan
- Isabelle Lavenir
- Jennifer Macdonald
- Sophie Morgan
- Manuel Schweighauser
- Yang Shi