# Mutant TDP-43 drives impairments in axonal transport and glycolysis in a mouse stem-cell-derived motor neuron model of amyotrophic lateral sclerosis (ALS)

## TL;DR

This study shows that a TDP-43 mutation in motor neurons leads to reduced cell survival, impaired axonal transport, and lower energy production, without causing protein clumping.

## Contribution

The study identifies novel links between TDP-43 dysfunction, axonal transport, and glycolysis in a mouse stem-cell-derived motor neuron model of ALS.

## Key findings

- TDP-43M337V causes reduced motor neuron viability and impaired axonal transport.
- TDP-43M337V leads to decreased basal glycolysis compared to wild-type controls.
- TDP-43 dysfunction occurs without protein mislocalization or aggregation in this model.

## Abstract

TDP-43 dysfunction is thought to be central to ALS pathogenesis. Studying mutations in the gene which encodes TDP-43, TARDBP, provides a valuable opportunity to gain insight into how TDP-43 dysfunction alters cellular homoeostasis. Our group has previously developed a TDP-43M337V mouse embryonic stem cell-derived motor neuron (mESC-MN) model, which expresses a single copy of the human TARDBP gene expressing the pathogenic M337V mutation at low levels. Here, we perform extensive phenotypic characterisation of this model, and show that TDP-43M337V leads to reduced MN viability, impaired axonal transport and reduced basal glycolysis compared to TDP-43WT controls. Altered neuronal viability and function occurs in the absence of TDP-43 mislocalisation or aggregation, suggesting ‘proteinopathy’ is downstream of these ALS-relevant phenotypes. These findings provide further support for a link between TDP-43 dyshomeostasis, cellular bioenergetics and axonal transport and suggest these pathways warrant further investigation as targets for therapeutic intervention.