Big Tau: Structure, Evolutionary Divergence, and Emerging Roles in Cytoskeletal Dynamics and Tauopathies

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Tau proteins are crucial for axonal structure and transport.
• Dysregulation of tau is linked to neurodegenerative diseases.
• The MAPT gene generates multiple tau isoforms via alternative splicing.

Purpose of the Study:

• To review current knowledge on Big tau, a high-molecular-weight tau isoform.
• To identify knowledge gaps regarding Big tau's function and regulation.
• To inspire research into Big tau's role in neurodegeneration and cancer.

Main Methods:

• Comparative sequence and biophysical analyses of the exon-4a insert.
• In vitro assays and modeling to assess Big tau's effect on aggregation.
• Review of transcriptomic and proteomic data.

Main Results:

• Big tau, with its exon-4a insert, is predominantly expressed in neurons with long axons and specific CNS regions.
• The exon-4a insert is acidic, intrinsically disordered, and may shield aggregation-prone tau motifs.
• Big tau's presence correlates with reduced tau aggregation in the peripheral nervous system and cerebellum.
• Alternative Big tau variants are found in cancerous tissues.

Conclusions:

• Big tau's exon-4a insert likely plays a structural role, reducing tau aggregation.
• This mechanism may explain regional specificity in tauopathies.
• Big tau's broader roles in cytoskeletal remodeling and potential in cancer require further study.
• Understanding Big tau regulation and in vivo function is critical for therapeutic development.