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

## TL;DR

Big tau, a high-molecular-weight tau isoform, may protect neurons by preventing harmful tau aggregation, offering new insights into neurodegenerative diseases.

## Contribution

The paper identifies Big tau's structural and functional role in suppressing tau aggregation and its potential therapeutic implications.

## Key findings

- Big tau is predominantly expressed in the peripheral and select central nervous system neurons.
- The exon-4a insert in Big tau shields aggregation-prone regions, reducing β-sheet-driven fibril formation.
- Big tau's anti-aggregation properties may explain the resistance of certain brain regions to tauopathies.

## Abstract

What are the main findings?
Inclusion of the large exon 4a insert generates Big tau, a high-molecular-weight isoform of tau that predominates in the peripheral nervous system and in select regions of the central nervous system.Exon 4a encodes about 250 amino acids that form a highly acidic, intrinsically disordered domain whose length is evolutionarily conserved despite marked divergence in the primary sequence.

Inclusion of the large exon 4a insert generates Big tau, a high-molecular-weight isoform of tau that predominates in the peripheral nervous system and in select regions of the central nervous system.

Exon 4a encodes about 250 amino acids that form a highly acidic, intrinsically disordered domain whose length is evolutionarily conserved despite marked divergence in the primary sequence.

What are the implications of the main findings?
Modeling suggests that the expansion of the projection domain in Big tau sterically and electrostatically shields β-sheet-forming regions implicated in pathological fibril assembly.Elucidating how this structural adaptation affects axons and suppresses tau aggregation provides insight into selective neuronal vulnerability and may inform strategies to engineer aggregation-resistant tau variants.

Modeling suggests that the expansion of the projection domain in Big tau sterically and electrostatically shields β-sheet-forming regions implicated in pathological fibril assembly.

Elucidating how this structural adaptation affects axons and suppresses tau aggregation provides insight into selective neuronal vulnerability and may inform strategies to engineer aggregation-resistant tau variants.

Tau proteins are microtubule-associated proteins that regulate axonal structure, dynamics, and transport, and their dysregulation underlies several neurodegenerative diseases. The MAPT gene produces multiple tau isoforms through alternative splicing, including the high-molecular-weight isoform known as Big tau, which contains an insert of the large 4a exon of approximately 250 amino acids. Big tau is predominantly expressed in neurons of the peripheral nervous system (PNS), cranial motor nuclei, and select neurons of the central nervous system (CNS) such as the cerebellum and brainstem. Developmental expression studies indicate a switch from low-molecular-weight isoforms of tau to Big tau during axonal maturation, suggesting that Big tau optimizes cytoskeletal dynamics to accommodate long axonal projections. Comparative sequence and biophysical analyses show that the exon-4a insert is highly acidic, intrinsically disordered, and evolutionarily conserved in its length but not its primary sequence, implying a structural role. Emerging modeling and in vitro assays suggest that the extended projection domain provided by the exon-4a insert spatially and electrostatically shields the aggregation-prone PHF6 and PHF6* motifs in tau’s microtubule-binding domain, thereby reducing β-sheet driven aggregation. This mechanism may explain why tauopathies that involve aggregation of tau have little effect on the PNS and specific regions of the CNS such as the cerebellum, where Big tau predominates. Transcriptomic and proteomic data further suggest that alternative Big tau variants, including 4a-L, are expressed in certain cancerous tissues, indicating broader roles in cytoskeletal remodeling beyond neurons. Despite its putative anti-aggregation properties, the physiological regulation, interaction partners, and in vivo mechanisms of Big tau remain poorly defined. This review summarizes what is known about Big tau and what is missing toward a better understanding of how expansion via inclusion of exon 4a modifies tau’s structural and functional properties. Our purpose is to inspire future studies that could lead to novel therapeutic strategies to mitigate tau aggregation in neurodegenerative diseases.