# cnnm-5 knockdown improves proteostasis of mutant Huntingtin protein in C. elegans

## TL;DR

Reducing the cnnm-5 gene in C. elegans decreases harmful protein buildup linked to Huntington's and Alzheimer's diseases, improving health and lifespan.

## Contribution

Identifies cnnm-5 as a novel genetic modifier that reduces mutant protein aggregation in neurodegenerative disease models.

## Key findings

- Knocking down cnnm-5 decreases mutant Huntingtin protein aggregation in C. elegans.
- cnnm-5 knockdown upregulates UPS and autophagy pathways, improving proteostasis.
- cnnm-5i also reduces beta amyloid misfolding in an Alzheimer's model, delaying paralysis.

## Abstract

Huntington's disease (HD) is an age-related neurodegenerative disease associated with the aggregation of mutant Huntingtin protein (mHTT). It is theorized that prevention or clearance of these aggregates through autophagy and the ubiquitin proteasome system (UPS) protects neurons from degeneration. Using a

C. elegans

model of HD, a small reverse genetic screen of 100 random genes on Chromosome 3 identified

cnnm-5

as a genetic modifier of mHTT accumulation. During development, loss of

cnnm-5

by RNAi (

cnnm-5

i) protects against mHTT accumulation, implicating

cnnm-5

as a negative regulator of protein aggregation prevention or clearance. Here we report that knocking down

cnnm-5

leads to decreased mHTT protein aggregation through the upregulation of the UPS and autophagy pathways, leading to increased lifespan. Further experimentation using a nematode model of Alzheimer's disease demonstrates

cnnm-5

i protects against paralysis by decreasing beta amyloid protein misfolding in body wall muscles.