# Tau destabilization in a familial deletion mutant K280 accelerates its fibrillization and enhances the seeding effect

## TL;DR

This study explores how a deletion in the tau protein affects its structure and aggregation, which could help in understanding and treating tau-related brain diseases.

## Contribution

The study reveals that the ΔK280 mutation destabilizes tau, accelerates fibril formation, and enhances cross-seeding effects.

## Key findings

- The ΔK280 mutant tau is more destabilized and loses intramolecular contacts compared to wild-type tau.
- Mutant tau forms fibrils faster and promotes higher cell-to-cell transmission than wild-type tau.
- Wild-type tau can be converted into mutant-like fibrils through cross-seeding with mutant seeds.

## Abstract

Tauopathies cover a range of neurodegenerative diseases in which natively unfolded tau protein aggregates and spreads in the brain during disease progression. To gain insights into the mechanism of tau structure and spreading, here, we examined the biochemical and cellular properties of human full-length wild-type and familial mutant tau, ΔK280, with a deletion at lysine 280. Our results showed that both wild-type and mutant tau are predominantly monomeric by analytical ultracentrifugation. The mutant tau may lose intramolecular contacts and is significantly destabilized assessed by cross-linking mass spectrometry and urea denaturation. Moreover, the mutant tau displayed accelerated fibril formation compared to the wild-type tau. Upon cross-seeding, the wild-type tau was seeded more easily by wild-type seeds than mutant seeds showing that homotypic seeding is more efficient. The wild-type tau was successfully converted to fibrils with mutant signatures by mutant seeds. Live cell cross-correlation fluorescence spectroscopy studies indicated that wild-type tau forms trimeric species and the mutant tau forms a larger assembly and processes higher cell-to-cell transmission. Overall, these findings shed light on the fundamental mechanisms of tau structure/stability, aggregation, and seeding to facilitate future therapeutic development for tauopathies.