The C291R Tau Variant Forms Different Types of Protofibrils

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Mutations in the MAPT gene are linked to tauopathies, but their pathological mechanisms remain unclear.
• Understanding tau aggregation is crucial for deciphering neurodegenerative disease pathways.

Purpose of the Study:

• To characterize the aggregation stages and conformational changes of the tau C291R mutation.
• To investigate the pathogenic mechanisms of this novel MAPT gene variant.

Main Methods:

• Atomic Force Microscopy (AFM) and negative-stained electron microscopy were used to visualize tau aggregates.
• Circular Dichroism (CD) spectroscopy was employed to analyze protein secondary structure.

Main Results:

• The tau-K18 C291R variant formed diverse aggregates, including granular oligomers and unique annular pore-like structures.
• Four distinct protofibril phenotypes were observed, differing from wild-type tau-K18.
• CD data indicated mutation-enhanced β-sheet propensity in tau-K18 C291R monomers.

Conclusions:

• The tau C291R mutation drives the formation of novel β-sheet-rich tau aggregates.
• The aggregation mechanism involves granular oligomers rearranging into unique protofibrillar structures.
• This study provides the first characterization of a genetic tau mutation involving a cysteine residue substitution.