2023
DOI: 10.3389/fnagi.2023.1151848
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A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations

Scott P. Allen,
Afnan Al Sultan,
Elaine Kabucho Kibirige
et al.

Abstract: 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 intermediate… Show more

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“…However, taking this into consideration, our data may reflect that there are underlying metabolic and mitochondrial deficits, which in the fibroblasts are at the baseline of what the cell type can deal with, as fibroblasts are relatively metabolically flexible and can use multiple substrates to maintain the broad mitochondrial parameters, which were measured in this study. 57 , 58 However, it would be interesting and important to investigate whether this would also be the case in neurons, which are generally metabolically less flexible.…”
Section: Discussionmentioning
confidence: 99%
“…However, taking this into consideration, our data may reflect that there are underlying metabolic and mitochondrial deficits, which in the fibroblasts are at the baseline of what the cell type can deal with, as fibroblasts are relatively metabolically flexible and can use multiple substrates to maintain the broad mitochondrial parameters, which were measured in this study. 57 , 58 However, it would be interesting and important to investigate whether this would also be the case in neurons, which are generally metabolically less flexible.…”
Section: Discussionmentioning
confidence: 99%