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

Journal article

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.

Authors: Carroll, E; Scaber, J; Pasniceanu, I; Dafinca, R; Gordon, D

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature [academic journals on nature.com]
• Journal: Cell Death & Disease
• Volume: 17
• Issue: 1
• Article number: 193
• Publication date: 2026-01-31
• Acceptance date: 2026-01-21
• DOI: 10.1038/s41419-026-08437-2
• EISSN: 2041-4889
• ISSN: 2041-4889
• Language: English
• Keywords: Amyotrophic lateral sclerosis; Axoplasmic transport; Glycolysis; Motor neuron; Mutant; Embryonic stem cell; Mutation; Bioenergetics; Cellular model