AUTHOR=Allen Scott P. , Al Sultan Afnan , Kabucho Kibirige Elaine , Tonkiss Erin , Hamer Keaton J. , Castelli Lydia M. , Lin Ya-Hui , Roscoe Sarah , Stefanidis Nikolaos , Mead Richard J. , Highley J. Robin , Cooper-Knock Johnathan , Hautbergue Guillaume M. , Heath Paul R. , Kirby Janine , Shaw Pamela J. 

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

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=15

YEAR=2023

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2023.1151848

DOI=10.3389/fnagi.2023.1151848

ISSN=1663-4365

ABSTRACT=<p>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.</p>