# Ubiquitin ligase Nedd4 regulates the abundance and toxicity of mutant huntingtin

## TL;DR

The E3 ubiquitin ligase Nedd4 helps reduce toxic mutant huntingtin levels in Huntington’s disease, and its reduced activity may worsen the disease.

## Contribution

This study identifies Nedd4 as a regulator of mutant huntingtin toxicity and suggests restoring Nedd4 activity as a potential HD therapy.

## Key findings

- Nedd4 ubiquitinates mutant huntingtin, promoting its clearance.
- Reduced Nedd4 levels increase mutant huntingtin toxicity in neurons and fly models.
- Impaired mTORC1 activity decreases Nedd4 levels, creating a feedback loop of mHtt accumulation.

## Abstract

Huntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of CAG repeats in the gene encoding huntingtin. Since accumulation of mutant huntingtin (mHtt) leads to dysfunction of numerous cellular pathways and toxicity, reducing levels of the mutant protein represents a key therapeutic objective in HD. We found that ubiquitination of mHtt by E3 ubiquitin ligase Nedd4 promotes clearance of the mutant protein. Knockdown of Nedd4 increased toxicity of mHtt in mouse primary neurons and in a fly model of HD, suggesting the protective role of Nedd4. Importantly, levels of Nedd4 were decreased in mHtt-expressing neurons through impaired mTORC1 activity, suggesting a feedback loop of mHtt accumulation and Nedd4 reduction that leads to accumulation and, ultimately, toxicity of mHtt. These findings suggest that restoring Nedd4 activity may offer a novel therapeutic opportunity for HD.

<strong>Ubiquitin ligase Nedd4 regulates the abundance and toxicity of mutant huntingtin.</strong>