Molecular mechanisms of neurodegeneration
Alzheimer's disease and Parkinson's disease are characterized by the presence of abnormal filamentous assemblies within some nerve cells. Similar assemblies are found in several related disorders. The events leading to filament formation or the mere presence of filaments are believed to produce nerve cell degeneration.
Our work has shown that the intraneuronal filaments found in these diseases are made of either microtubule-associated protein tau or α-synuclein.
In Alzheimer's disease hyperphosphorylated tau protein forms the major component of paired helical and straight filaments. The discovery of mutations in the tau gene in inherited frontotemporal dementia has firmly established that dysfunction of tau protein can cause neurodegeneration and dementia.
The α-synuclein gene is mutated in rare cases of inherited Parkinson's disease and α-synuclein is the major component of the filamentous lesions that characterize Parkinson's disease and other Lewy body disorders, as well as multiple system atrophy. It is therefore central to the pathogenesis of these diseases.
Current work is aimed at developing experimental animal models of tauopathies and α-synucleinopathies and at identifying disease modifiers.
- Clavaguera, F., Akatsu, H., Fraser, G., Crowther, R.A., Frank, S., Hench, J., Probst, A., Winkler, D.T., Reichwald, J., Staufenbiel, M., Ghetti, B., Goedert, M., and Tolnay, M. (2013)
Brain homogenates from human tauopathies induce tau inclusions in mouse brain.
Proc. Natl. Acad. Sci. USA. 110: 9535-9540.
- Goedert, M., Spillantini, M.G., Del Tredici. K., and Braak, H. (2013)
100 years of Lewy pathology
Nat. Rev. Neurol. 9: 13-24.
- Spillantini, M.G., and Goedert, M. (2013)
Tau pathology and neurodegeneration.
Lancet Neurol. 12: 609-622.
- Isabelle Lavenir
- Jennifer Macdonald
- Rene Frank
- Ben Falcon
- Sophie Morgan
- Juan Fan
- Byron Andrews
- Manuel Schweighauser