Structural basis of the interplay between α-synuclein and Tau in regulating pathological amyloid aggregation

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Protein aggregation, including alpha-synuclein (α-syn) and Tau, is central to neurodegenerative diseases like Parkinson's and Alzheimer's.
• Co-deposition of α-syn and Tau in affected brains suggests potential interactions influencing disease pathology.
• Understanding the molecular mechanisms of α-syn and Tau interplay is crucial for developing therapeutic strategies.

Purpose of the Study:

• To investigate the synergistic effect of α-syn and Tau on amyloid fibrillation.
• To elucidate the molecular basis of the interaction between α-syn and Tau variants.
• To determine the role of α-syn C-terminal charge and phosphorylation in Tau aggregation.

Main Methods:

• In vitro amyloid fibrillation assays using monomeric α-syn and Tau variants (Tau23, K19).
• Nuclear Magnetic Resonance (NMR) spectroscopy to identify protein interaction sites.
• Site-directed mutagenesis to assess the role of α-syn C-terminus and S129 phosphorylation.

Main Results:

• Monomeric α-syn and Tau variants synergistically promoted amyloid fibrillation and co-aggregation in vitro.
• NMR revealed direct interaction between the negatively charged C terminus of α-syn and Tau23/K19.
• Deletion of α-syn's C terminus abolished Tau binding and synergistic fibrillation; S129D substitution enhanced Tau aggregation.

Conclusions:

• The C terminus of α-syn directly interacts with Tau, driving synergistic amyloid fibrillation.
• Phosphorylation at Ser129 of α-syn enhances its ability to promote Tau aggregation.
• This α-syn-Tau cross-talk provides a molecular basis for their co-pathology in neurodegenerative diseases.