Journal
METABOLITES
Volume 9, Issue 6, Pages -Publisher
MDPI
DOI: 10.3390/metabo9060113
Keywords
Huntington's disease; neurodegeneration; vitamin B5; acetyl-coenzyme A; brain energy metabolism; acetylcholine biosynthesis; metabolomics; bioinformatics; data visualisation; data analytics
Categories
Funding
- Endocore Research Trust [61047]
- Maurice and Phyllis Paykel Trust [3627036]
- Lottery Health New Zealand [3626585, 3702766]
- Maurice Wilkins Centre for Molecular Biodiscovery (Tertiary Education Commission) [9341-3622506]
- University of Auckland-Doctoral Student PReSS funding [JXU058]
- Oakley Mental Health Research Foundation [3456030, 3627092, 3701339, 3703253, 3702870]
- Ministry of Business, Innovation Employment [UOAX0815]
- New Zealand Neurological Foundation
- Health Research Council of New Zealand
- University of Manchester
- Maurice Wilkins Centre for Molecular Biodiscovery
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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.
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