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<p>TDP-43 dysfunction is thought to be central to ALS pathogenesis. Studying mutations in the gene which encodes TDP-43, <i>TARDBP</i>, provides a valuable opportunity to gain insight into how TDP-43 dysfunction alters cellular homoeostasis. Our group has previously developed a TDP-43<sup>M337V</sup> mouse embryonic stem cell-derived motor neuron (mESC-MN) model, which expresses a single copy of the human <i>TARDBP</i> gene expressing the pathogenic M337V mutation at low levels. Here, we perform extensive phenotypic characterisation of this model, and show that TDP-43<sup>M337V</sup> leads to reduced MN viability, impaired axonal transport and reduced basal glycolysis compared to TDP-43<sup>WT</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月31日

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  • Emily Carroll,
  • Jakub Scaber,
  • Iris-Stefania Pasniceanu,
  • Ruxandra Dafinca,
  • David Gordon,
  • Ana Candalija,
  • Kevin Talbot

摘要

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.