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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
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 fibrob...
| Autores principales: | , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
Frontiers Media S.A.
2023
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| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10213779/ https://www.ncbi.nlm.nih.gov/pubmed/37251807 http://dx.doi.org/10.3389/fnagi.2023.1151848 |
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| 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. |
| author_facet | 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. |
| author_sort | Allen, Scott P. |
| collection | PubMed |
| description | 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. |
| format | Online Article Text |
| id | pubmed-10213779 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2023 |
| publisher | Frontiers Media S.A. |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-102137792023-05-27 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. 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. Front Aging Neurosci Aging Neuroscience 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. Frontiers Media S.A. 2023-05-11 /pmc/articles/PMC10213779/ /pubmed/37251807 http://dx.doi.org/10.3389/fnagi.2023.1151848 Text en Copyright © 2023 Allen, Al Sultan, Kabucho Kibirige, Tonkiss, Hamer, Castelli, Lin, Roscoe, Stefanidis, Mead, Highley, Cooper-Knock, Hautbergue, Heath, Kirby and Shaw. https://creativecommons.org/licenses/by/4.0/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. |
| spellingShingle | Aging Neuroscience 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. A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations |
| title | A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations |
| title_full | A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations |
| title_fullStr | A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations |
| title_full_unstemmed | A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations |
| title_short | A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations |
| title_sort | y374x tdp43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and tca cycle intermediate alterations |
| topic | Aging Neuroscience |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10213779/ https://www.ncbi.nlm.nih.gov/pubmed/37251807 http://dx.doi.org/10.3389/fnagi.2023.1151848 |
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