TY - JOUR
T1 - Coenzyme A-Dependent Tricarboxylic Acid Cycle Enzymes Are Decreased in Alzheimer’s Disease Consistent With Cerebral Pantothenate Deficiency
AU - Sang, Crystal
AU - Philbert, Sasha
AU - Hartland, Danielle
AU - Unwin, Richard
AU - Dowsey, Andrew
AU - Xu, Jingshu
AU - Cooper, Garth JS
N1 - Funding Information:
We acknowledge the following funding sources: Endocore Research Trust (NZ; 60187); the Lee Trust (NZ); Oakley Mental Health Research Foundation (NZ; 3456030, 3627092, 3701339, 3703253, 3702879); Maurice and Phyllis Paykel Trust (3627036); UKRI Medical Research Council (MR/N0284457/1); NZ Ministry of Business, Innovation & Employment (UOAX0815, CONT-57362-ENDRP-UOA); The University of Manchester; Northwest Regional Development Agency through a combined programme grant to CADET; and facilitation by the Greater Manchester Comprehensive Local Research Network.
Publisher Copyright:
Copyright © 2022 Sang, Philbert, Hartland, Unwin, Dowsey, Xu and Cooper.
PY - 2022/6/10
Y1 - 2022/6/10
N2 - 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.
AB - 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.
KW - coenzyme A (CoA)
KW - human brain
KW - pantothenic acid/vitamin B5
KW - pyruvate dehydrogenase complex
KW - sporadic Alzheimer’s disease
KW - tricarboxylic acid cycle (TCA cycle)
U2 - 10.3389/fnagi.2022.893159
DO - 10.3389/fnagi.2022.893159
M3 - Article
C2 - 35754968
VL - 14
SP - 893159
JO - Frontiers in aging neuroscience
JF - Frontiers in aging neuroscience
SN - 1663-4365
IS - 893159
M1 - 893159
ER -