# Deubiquitinating Enzymes Ubiquitin-Specific Proteases 7 and 10 Regulate TAU Aggregation

## TL;DR

This study shows that inhibiting enzymes USP7 and USP10 reduces TAU protein aggregation, a key feature of Alzheimer's disease.

## Contribution

The novel finding is that USP7 and USP10 regulate TAU aggregation through ubiquitin-dependent pathways.

## Key findings

- Knockdown of Usp7 and Usp10 reduced seeded TAU aggregation in mouse cortical cultures.
- Inhibition of Usp7 and Usp10 increased polyubiquitination of residual TAU inclusions.
- Effects were observed in both cortical and hippocampal slice cultures from rTg4510 mice.

## Abstract

Accumulation of the microtubule-associated protein TAU into inclusions is a hallmark of tauopathies including Alzheimer’s disease (AD), potentially driven by impaired protein degradation and dysregulated ubiquitination. To explore the role of deubiquitinating enzymes (DUBs), we performed siRNA knockdown screens targeting 93 murine DUBs in rTg4510 cortical cultures. Knockdown and pharmacological inhibition of the ubiquitin-specific proteases 7 (Usp7) and 10 (Usp10) significantly reduced seeded TAU aggregation without affecting soluble TAU levels. These effects were observed in both cortical and organotypic hippocampal slice cultures from rTg4510 mice, as well as in wildtype neurons seeded with AD-derived pathological TAU. Inhibition of Usp7 and Usp10 was associated with increased polyubiquitination of residual TAU inclusions in rTg4510 cortical cultures. These findings suggest that Usp7 and Usp10 contribute to pathological TAU accumulation by modulating ubiquitin-dependent degradation pathways. Targeting USP7 and USP10 may offer a novel therapeutic strategy for AD and related tauopathies.