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

Allen, Scott P. and Al Sultan, Afnan and Kabucho Kibirige, Elaine and Tonkiss, Erin and Hamer, Keaton J. and Castelli, Lydia M. and Lin, Ya-Hui and Roscoe, Sarah and Stefanidis, Nikolaos and Mead, Richard J. and Highley, J. Robin and Cooper-Knock, Johnathan and Hautbergue, Guillaume M. and Heath, Paul R. and Kirby, Janine and Shaw, Pamela J. (2023) A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations. Frontiers in Aging Neuroscience, 15. ISSN 1663-4365

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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 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.

Item Type: Article
Subjects: STM Digital Press > Medical Science
Depositing User: Unnamed user with email support@stmdigipress.com
Date Deposited: 05 Sep 2024 11:25
Last Modified: 05 Sep 2024 11:25
URI: http://publications.articalerewriter.com/id/eprint/1348

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