A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations

A p.Y374X truncation in TARDBP was recently shown to reduce expression of TDP43 in fibroblasts isolated from ALS cases. In this follow up study focused on assessing the downstream phenotypic consequences of loss of TDP43 in the context of the truncation, we have shown a striking effect on the fibroblast metabolic profile. Phenotypic metabolic screening uncovered a distinct metabolic profile in TDP43-Y374X fibroblasts compared to controls, which was driven by alterations in key metabolic checkpoint intermediates including pyruvate, alpha-ketoglutarate and succinate. These metabolic alterations were confirmed using transcriptomics and bioenergetic flux analysis. These data suggest that TDP43 truncation directly compromises glycolytic and mitochondrial function, identifying potential therapeutic targets for mitigating the effects of TDP43-Y374X truncation.

Automated summary

A recent study found that truncation p.Y374X in TARDBP reduces expression of TDP43 in fibroblasts from ALS cases. In this follow-up study, we have shown that this truncation has a striking effect on the metabolic profile of fibroblasts. Phenotypic metabolic screening revealed distinct metabolic alterations in TDP43-Y374X fibroblasts, including changes in key metabolic intermediates. These findings suggest that TDP43 truncation directly impairs glycolytic and mitochondrial function, indicating potential therapeutic targets for mitigating its effects.