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

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.

Metadata

Item Type:	Article
Authors/Creators:	Allen, S.P. https://orcid.org/0000-0003-4418-7375 Al Sultan, A. Kabucho Kibirige, E. Tonkiss, E. Hamer, K.J. Castelli, L.M. Lin, Y.-H. Roscoe, S. Stefanidis, N. Mead, R.J. Highley, J.R. Cooper-Knock, J. https://orcid.org/0000-0002-0873-8689 Hautbergue, G.M. Heath, P.R. Kirby, J. https://orcid.org/0000-0002-7468-5917 Shaw, P.J. https://orcid.org/0000-0002-8925-2567
Copyright, Publisher and Additional Information:	© 2023 Allen, Al Sultan, Kabucho Kibirige, Tonkiss, Hamer, Castelli, Lin, Roscoe, Stefanidis, Mead, Highley, Cooper-Knock, Hautbergue, Heath, Kirby and Shaw. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. https://creativecommons.org/licenses/by/4.0/
Keywords:	ALS; fibroblasts; metabolism; pyruvate; TCA; transcriptomics; metabolomics
Dates:	Published: 11 May 2023 Published (online): 11 May 2023 Accepted: 18 April 2023
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield)
Funding Information:	Funder Grant number WELLCOME TRUST (THE) 216596/Z/19/Z National Institute for Health Research IS-BRC-1215-20017 ACADEMY OF MEDICAL SCIENCES SBF005\1064 MOTOR NEURONE DISEASE ASSOCIATION Allen/Oct15/956-799
Depositing User:	Symplectic Sheffield
Date Deposited:	05 Jun 2023 16:01
Last Modified:	05 Jun 2023 16:01
Status:	Published
Publisher:	Frontiers Media SA
Refereed:	Yes
Identification Number:	10.3389/fnagi.2023.1151848
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:199745

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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

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