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Tau protein assembles into isoform- and disulfide-dependent polymorphic fibrils with distinct structural properties
Yoshiaki Furukawa1, Kumi Kaneko, Nobuyuki Nukina
1Department of Chemistry, Keio University, Yokohama, Kanagawa 223-8522, Japan. furukawa@chem.keio.ac.jp
The Journal of Biological Chemistry
|June 11, 2011
Summary
The study reveals how Tau protein
Area of Science:
- Neuroscience
- Biochemistry
- Structural Biology
Background:
- Tauopathies are neurodegenerative diseases characterized by abnormal Tau protein aggregation.
- The structural basis for Tau fibril polymorphism in different tauopathies is not well understood.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the formation of polymorphic Tau fibrils.
- To determine the role of Tau isoforms and thiol-disulfide status in fibril structure.
Main Methods:
- In vitro fibrillation assays using full-length Tau isoforms.
- Analysis of disulfide bond formation and its impact on Tau structure.
- Investigating cross-seeded fibrillation between different Tau isoforms.
Main Results:
- Thiol-disulfide status and Tau isoform composition dictate Tau fibril structure and morphology.
- Two key regions in Tau act as structural blocks for the fibril core.
- Combinatorial interactions between these blocks, influenced by disulfide status, generate polymorphic fibrils.
- Cross-seeding between different Tau isoforms leads to increased structural diversity.
Conclusions:
- Tau fibril polymorphism arises from combinatorial interactions between multiple Tau sequence regions.
- These interactions are dependent on both Tau isoform and thiol-disulfide status.
- This provides a molecular framework for understanding structural diversity in tauopathies.
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