Functional classification of tauopathy strains reveals the role of protofilament core residues

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Diverse tauopathies are caused by distinct tau amyloid assemblies, which are difficult to classify rapidly.
• Tau proteins function as prions, with different strains causing unique and transmissible neuropathology.

Purpose of the Study:

• To develop a method for rapid classification of tau prion strains.
• To identify critical amino acid sequences involved in tau prion propagation and strain discrimination.

Main Methods:

• Cryo-electron microscopy was used to determine the structure of a yellow fluorescent protein (YFP)-tagged tau strain.
• Sequential alanine substitution scanning within the tau repeat domain (RD) was employed to assess monomer incorporation into existing aggregates.
• Recombinant tau seeds and brain lysates from four tauopathies were analyzed using the alanine scan method.

Main Results:

• The alanine scan method robustly discriminated between different tau strains by identifying critical sequences for monomer incorporation.
• Biosensors created from wild-type tau RD (amino acids 246 to 408) successfully differentiated strains.
• Analysis of 22 brain lysates clustered cases by neuropathological syndrome and revealed the role of specific amino acids in protofilament structures.

Conclusions:

• The alanine scan method provides a robust approach for discriminating tau prion strains based on their amino acid requirements for replication.
• This technique facilitates the classification of distinct tau assemblies, offering insights into the molecular basis of diverse tauopathies.
• The findings advance the understanding of tau prion propagation and have implications for diagnosing and potentially treating tauopathies.