Dataset Information

Cerebral Vitamin B5 (D-Pantothenic Acid) Deficiency as a Potential Cause of Metabolic Perturbation and Neurodegeneration in Huntington's Disease.

ABSTRACT: Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the HTT gene. HD usually manifests in mid-life with loss of GABAergic projection neurons from the striatum accompanied by progressive atrophy of the putamen followed by other brain regions, but linkages between the genetics and neurodegeneration are not understood. We measured metabolic perturbations in HD-human brain in a case-control study, identifying pervasive lowering of vitamin B5, the obligatory precursor of coenzyme A (CoA) that is essential for normal intermediary metabolism. Cerebral pantothenate deficiency is a newly-identified metabolic defect in human HD that could potentially: (i) impair neuronal CoA biosynthesis; (ii) stimulate polyol-pathway activity; (iii) impair glycolysis and tricarboxylic acid cycle activity; and (iv) modify brain-urea metabolism. Pantothenate deficiency could lead to neurodegeneration/dementia in HD that might be preventable by treatment with vitamin B5.

SUBMITTER: Patassini S

PROVIDER: S-EPMC6630497 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Cerebral Vitamin B5 (D-Pantothenic Acid) Deficiency as a Potential Cause of Metabolic Perturbation and Neurodegeneration in Huntington's Disease.

Patassini Stefano S Begley Paul P Xu Jingshu J Church Stephanie J SJ Kureishy Nina N Reid Suzanne J SJ Waldvogel Henry J HJ Faull Richard L M RLM Snell Russell G RG Unwin Richard D RD Cooper Garth J S GJS

Metabolites 20190611 6

Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the <i>HTT</i> gene. HD usually manifests in mid-life with loss of GABAergic projection neurons from the striatum accompanied by progressive atrophy of the putamen followed by other brain regions, but linkages between the genetics and neurodegeneration are not understood. We measured metabolic perturbations in HD-human brain in a case-control study, identifying pervasive lowering of vitamin B5 ...[more]

PMID: 31212603

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Project description:Pantothenic acid deficiency (PAD) in animals causes growth depression, fasting hypoglycemia and impaired lipid and glucose metabolism. However, a systematic multi-omics analysis of effects of PAD on hepatic function has apparently not been reported. We investigated liver proteome and metabolome changes induced by PAD to explain its effects on growth and liver metabolic disorders. Pekin ducks (1-d-old, n = 128) were allocated into 2 groups, with 8 replicates and 8 birds per replicate. For 16 d, all ducks had ad libitum access to either a PAD or a pantothenic acid adequate (control, CON) diet, formulated by supplementing a basal diet with 0 or 8 mg pantothenic acid/kg of diet, respectively. Liver enlargement, elevated liver glycogen concentrations and decreased liver concentrations of triglyceride and unsaturated fatty acids were present in the PAD group compared to the CON group. Based on integrated liver proteomics and metabolomics, PAD mainly affected glycogen synthesis and degradation, glycolysis and gluconeogenesis, tricarboxylic acid (TCA) cycle, peroxisome proliferator-activated receptor (PPAR) signaling pathway, fatty acid beta oxidation, and oxidative phosphorylation. Selected proteins were confirmed by Western blotting. Downregulation of proteins and metabolites involved in glycogen synthesis and degradation, glycolysis and gluconeogenesis implied that these processes were impaired in PAD ducks, which could have contributed to fasting hypoglycemia, liver glycogen storage, insufficient ATP production, and growth retardation. In contrast, PAD also upregulated proteins and metabolites involved in fatty acid beta oxidation, the TCA cycle, and oxidative phosphorylation processes in the liver; presumably compensatory responses to produce ATP. We inferred that PAD decreased liver triglyceride and unsaturated fatty acids by activating fatty acid beta oxidation and impairing unsaturated fatty acid synthesis. These findings contributed to our understanding of the mechanisms of PAD-induced changes in hepatic metabolism.

Dataset Information

Cerebral Vitamin B5 (D-Pantothenic Acid) Deficiency as a Potential Cause of Metabolic Perturbation and Neurodegeneration in Huntington's Disease.

Publications

Cerebral Vitamin B5 (D-Pantothenic Acid) Deficiency as a Potential Cause of Metabolic Perturbation and Neurodegeneration in Huntington's Disease.

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