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Coenzyme A-Dependent Tricarboxylic Acid Cycle Enzymes Are Decreased in Alzheimer’s Disease Consistent With Cerebral Pantothenate Deficiency
Sporadic Alzheimer’s disease (sAD) is the commonest cause of age-related neurodegeneration and dementia globally, and a leading cause of premature disability and death. To date, the quest for a disease-modifying therapy for sAD has failed, probably reflecting our incomplete understanding of aetiolog...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9232186/ https://www.ncbi.nlm.nih.gov/pubmed/35754968 http://dx.doi.org/10.3389/fnagi.2022.893159 |
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author | Sang, Crystal Philbert, Sasha A. Hartland, Danielle Unwin, Richard. D Dowsey, Andrew W. Xu, Jingshu Cooper, Garth J. S. |
author_facet | Sang, Crystal Philbert, Sasha A. Hartland, Danielle Unwin, Richard. D Dowsey, Andrew W. Xu, Jingshu Cooper, Garth J. S. |
author_sort | Sang, Crystal |
collection | PubMed |
description | Sporadic Alzheimer’s disease (sAD) is the commonest cause of age-related neurodegeneration and dementia globally, and a leading cause of premature disability and death. To date, the quest for a disease-modifying therapy for sAD has failed, probably reflecting our incomplete understanding of aetiology and pathogenesis. Drugs that target aggregated Aβ/tau are ineffective, and metabolic defects are now considered to play substantive roles in sAD pathobiology. We tested the hypothesis that the recently identified, pervasive cerebral deficiency of pantothenate (vitamin B5) in sAD, might undermine brain energy metabolism by impairing levels of tricarboxylic acid (TCA)-cycle enzymes and enzyme complexes, some of which require the pantothenate-derived cofactor, coenzyme A (CoA) for their normal functioning. We applied proteomics to measure levels of the multi-subunit TCA-cycle enzymes and their cytoplasmic homologues. We analysed six functionally distinct brain regions from nine sAD cases and nine controls, measuring 33 cerebral proteins that comprise the nine enzymes of the mitochondrial-TCA cycle. Remarkably, we found widespread perturbations affecting only two multi-subunit enzymes and two enzyme complexes, whose function is modulated, directly or indirectly by CoA: pyruvate dehydrogenase complex, isocitrate dehydrogenase, 2-oxoglutarate dehydrogenase complex, and succinyl-CoA synthetase. The sAD cases we studied here displayed widespread deficiency of pantothenate, the obligatory precursor of CoA. Therefore, deficient cerebral pantothenate can damage brain-energy metabolism in sAD, at least in part through impairing levels of these four mitochondrial-TCA-cycle enzymes. |
format | Online Article Text |
id | pubmed-9232186 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92321862022-06-25 Coenzyme A-Dependent Tricarboxylic Acid Cycle Enzymes Are Decreased in Alzheimer’s Disease Consistent With Cerebral Pantothenate Deficiency Sang, Crystal Philbert, Sasha A. Hartland, Danielle Unwin, Richard. D Dowsey, Andrew W. Xu, Jingshu Cooper, Garth J. S. Front Aging Neurosci Aging Neuroscience Sporadic Alzheimer’s disease (sAD) is the commonest cause of age-related neurodegeneration and dementia globally, and a leading cause of premature disability and death. To date, the quest for a disease-modifying therapy for sAD has failed, probably reflecting our incomplete understanding of aetiology and pathogenesis. Drugs that target aggregated Aβ/tau are ineffective, and metabolic defects are now considered to play substantive roles in sAD pathobiology. We tested the hypothesis that the recently identified, pervasive cerebral deficiency of pantothenate (vitamin B5) in sAD, might undermine brain energy metabolism by impairing levels of tricarboxylic acid (TCA)-cycle enzymes and enzyme complexes, some of which require the pantothenate-derived cofactor, coenzyme A (CoA) for their normal functioning. We applied proteomics to measure levels of the multi-subunit TCA-cycle enzymes and their cytoplasmic homologues. We analysed six functionally distinct brain regions from nine sAD cases and nine controls, measuring 33 cerebral proteins that comprise the nine enzymes of the mitochondrial-TCA cycle. Remarkably, we found widespread perturbations affecting only two multi-subunit enzymes and two enzyme complexes, whose function is modulated, directly or indirectly by CoA: pyruvate dehydrogenase complex, isocitrate dehydrogenase, 2-oxoglutarate dehydrogenase complex, and succinyl-CoA synthetase. The sAD cases we studied here displayed widespread deficiency of pantothenate, the obligatory precursor of CoA. Therefore, deficient cerebral pantothenate can damage brain-energy metabolism in sAD, at least in part through impairing levels of these four mitochondrial-TCA-cycle enzymes. Frontiers Media S.A. 2022-06-10 /pmc/articles/PMC9232186/ /pubmed/35754968 http://dx.doi.org/10.3389/fnagi.2022.893159 Text en Copyright © 2022 Sang, Philbert, Hartland, Unwin, Dowsey, Xu and Cooper. 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 Sang, Crystal Philbert, Sasha A. Hartland, Danielle Unwin, Richard. D Dowsey, Andrew W. Xu, Jingshu Cooper, Garth J. S. Coenzyme A-Dependent Tricarboxylic Acid Cycle Enzymes Are Decreased in Alzheimer’s Disease Consistent With Cerebral Pantothenate Deficiency |
title | Coenzyme A-Dependent Tricarboxylic Acid Cycle Enzymes Are Decreased in Alzheimer’s Disease Consistent With Cerebral Pantothenate Deficiency |
title_full | Coenzyme A-Dependent Tricarboxylic Acid Cycle Enzymes Are Decreased in Alzheimer’s Disease Consistent With Cerebral Pantothenate Deficiency |
title_fullStr | Coenzyme A-Dependent Tricarboxylic Acid Cycle Enzymes Are Decreased in Alzheimer’s Disease Consistent With Cerebral Pantothenate Deficiency |
title_full_unstemmed | Coenzyme A-Dependent Tricarboxylic Acid Cycle Enzymes Are Decreased in Alzheimer’s Disease Consistent With Cerebral Pantothenate Deficiency |
title_short | Coenzyme A-Dependent Tricarboxylic Acid Cycle Enzymes Are Decreased in Alzheimer’s Disease Consistent With Cerebral Pantothenate Deficiency |
title_sort | coenzyme a-dependent tricarboxylic acid cycle enzymes are decreased in alzheimer’s disease consistent with cerebral pantothenate deficiency |
topic | Aging Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9232186/ https://www.ncbi.nlm.nih.gov/pubmed/35754968 http://dx.doi.org/10.3389/fnagi.2022.893159 |
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