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Tau polymerization: role of the amino terminus
T Chris Gamblin1, Robert W Berry, Lester I Binder
1Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611-3008, USA.
Abstract:
The abnormal polymerization of the tau molecule into insoluble filaments is a seminal event in the neurodegenerative process underlying Alzheimer's disease. Previous experimentation has shown that the microtubule-binding repeat region of the molecule is vital for its ability to polymerize in vitro into filaments similar to those found in Alzheimer's disease. However, it is becoming clear that regions outside the microtubule-binding repeat, such as exons 2 and 3 and the carboxy-terminal tail, can greatly influence its polymerization. Since it has been previously postulated that the amino terminus of tau could be involved in generating pathological conformations in the disease state, its role in the polymerization process was investigated. This report demonstrates that the removal of the amino terminus greatly inhibits the polymerization of the tau molecule, reducing both the rate and extent of polymerization. These results support the hypothesis that the ability of tau to form specific conformations involving the amino terminus is an early event in the formation of tau polymers in the disease state. Furthermore, the mutation of arginine 5 to leucine ((R)5(L)), mimicking an amino-terminal tau mutation found in a single case of FTDP-17, enhances the polymerization of the tau molecule. Therefore, the amino terminus of the tau molecule, while largely overlooked in studies of its polymerization, is a significant contributor to the polymerization process.
Insights
The tau molecule's amino terminus significantly impacts its polymerization, a key process in Alzheimer's disease. Removing this end inhibits filament formation, while specific mutations enhance it, highlighting its crucial role.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Abnormal tau polymerization into filaments is central to Alzheimer's disease pathogenesis.
- While the microtubule-binding repeat is known to be vital for tau polymerization, other regions also influence this process.
- The role of the tau amino terminus in pathological polymerization has been largely overlooked.
Purpose of the Study:
- To investigate the role of the tau amino terminus in the polymerization process.
- To determine if the amino terminus is involved in generating pathological tau conformations.
Main Methods:
- Investigated tau polymerization by removing the amino terminus.
- Studied the effect of an amino-terminal mutation (R5L), mimicking FTDP-17, on tau polymerization.
Main Results:
- Removal of the tau amino terminus significantly inhibited both the rate and extent of polymerization.
- The R5L mutation, mimicking a frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) mutation, enhanced tau polymerization.
- These findings indicate the amino terminus is crucial for tau polymerization.
Conclusions:
- The tau amino terminus plays a significant role in its polymerization process.
- Specific conformations involving the amino terminus are likely an early event in tau polymer formation in Alzheimer's disease.
- The amino terminus is a critical, yet underappreciated, factor in tau polymerization and associated neurodegeneration.