# Disruption of the nascent polypeptide-associated complex leads to reduced polyglutamine aggregation and toxicity

## TL;DR

Disrupting a protein complex called NAC reduces harmful protein clumps linked to neurodegenerative diseases.

## Contribution

NAC disruption is shown to reduce polyglutamine aggregation and toxicity, suggesting a new therapeutic strategy.

## Key findings

- NAC disruption improves cell viability in polyglutamine-expressing cells.
- NAC disruption delays and reduces polyglutamine aggregation and alters its morphology.
- NAC disruption affects de novo yeast prion induction.

## Abstract

The nascent polypeptide-associate complex (NAC) is a heterodimeric chaperone complex that binds near the ribosome exit tunnel and is the first point of chaperone contact for newly synthesized proteins. Deletion of the NAC induces embryonic lethality in many multi-cellular organisms. Previous work has shown that the deletion of the NAC rescues cells from prion-induced cytotoxicity. This counterintuitive result led us to hypothesize that NAC disruption would improve viability in cells expressing human misfolding proteins. Here, we show that NAC disruption improves viability in cells expressing expanded polyglutamine and also leads to delayed and reduced aggregation of expanded polyglutamine and changes in polyglutamine aggregate morphology. Moreover, we show that NAC disruption leads to changes in de novo yeast prion induction. These results indicate that the NAC plays a critical role in aggregate organization as a potential therapeutic target in neurodegenerative disorders.