Precision proteoform design for 4R tau isoform selective templated aggregation.

Tauopathies, such as Alzheimer’s disease, are neurodegenerative diseases caused by the buildup and spread of misfolded tau proteins in the brain. Normally, tau proteins stabilize the structure and functions of neurons, but in tauopathies, they misfold, aggregate together, and spread between neurons in a prion-like manner. This results in amplified neuronal damage and contributes to driving disease progression. A particular form of tau, called 4R tau, is especially prone to aggregation in certain tauopathies, but the reasons for this are unknown. In this study, researchers developed a synthetic tau peptide that mimics the behavior of disease-associated tau aggregates. This peptide selectively targets 4R tau, without interacting with other tau isoforms. Using computer simulations and cell-based experiments, they identified specific molecular structures and amino acid spans within 4R tau that make it more likely to aggregate. These findings showed that even small amino acid changes to these critical regions can dramatically alter tau behavior to pathogenic. For example, they found that replacing a single amino acid in one of these regions caused 4R tau to significantly reduce its ability to misfold and form aggregates, providing a potential strategy to prevent the spread of tauopathies. Conversely, modifying other tau isoforms to resemble these 4R tau regions restored tau’s aggregation capability, confirming the importance of these structural features. Additionally, they studied how the synthetic peptide triggers tau aggregation in human cells. The peptide reliably caused 4R tau to misfold, bind together, and propagate across cells, mimicking the spread of tauopathies. They also explored ways to block this process using a nanobody that bound selectively to specific tau regions. The nanobody significantly reduced tau aggregation in cells, offering a promising avenue for therapeutic development. In addition to studying tau misfolding, they discovered that tau aggregates disrupt other cellular components, such as lipids, suggesting broader impacts on brain cell functions. These findings provide a more comprehensive understanding of how tau aggregation harms neurons and contributes to disease progression. This research highlights the molecular details driving 4R tau aggregation, offering new insights into how tauopathies develop. By pinpointing specific amino acids and structural features, they have uncovered potential strategies for preventing tau misfolding and spread. These findings could help lead to targeted therapies that could slow or stop the progression of tauopathies.