期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1862, 期 9, 页码 1650-1662出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2016.06.002
关键词
Neurodegenerative disease; Huntington's disease; Polyol pathway; Brain urea metabolism; Metabolic brain disease; Inositol pathway
资金
- Endocore Research Trust [61047]
- Cure Huntington's Disease Initiative (CHDI) [A-8247]
- Maurice and Phyllis Paykel Trust [3627036]
- Lottery Health New Zealand [3626585, 3702766]
- Maurice Wilkins Centre for Molecular Biodiscovery [through a Tertiary Education Commission grant] [9341-3622506]
- Health Research Council of New Zealand [3338701]
- 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
- Medical Research Council [UK] [MR/L010445/1, MR/L011093/1]
- Alzheimer's Research UK [ARUK-PPG2014B-7]
- University of Manchester
- Central Manchester (NHS) Foundation Trust
- Northwest Regional Development Agency through a combined programme grant
Huntington's disease (HD) is a genetically-mediated neurodegenerative disorder wherein the aetiological defect is a mutation in the Huntington's gene (HTT), which alters the structure of the huntingtin protein (Htt) through lengthening of its polyglutamine tract, thus initiating a cascade that ultimately leads to premature death. However, neurodegeneration typically manifests in HD only in middle age, and mechanisms linking the causative mutation to brain disease are poorly understood. Brain metabolism is severely perturbed in HD, and some studies have indicated a potential role for mutant Htt as a driver of these metabolic aberrations. Here, our objective was to determine the effects of HD on brain metabolism by measuring levels of polar metabolites in regions known to undergo varying degrees of damage. We performed gas-chromatography/mass spectrometry-based metabolomic analyses in a case-control study of eleven brain regions in short post-mortem-delay human tissue from nine well-characterized HD patients and nine matched controls. In each patient, we measured metabolite content in representative tissue-samples from eleven brain regions that display varying degrees of damage in HD, thus identifying the presence and abundance of 63 different metabolites from several molecular classes, including carbohydrates, amino acids, nucleosides, and neurotransmitters. Robust alterations in regional brain metabolite abundances were observed in HD patients: these included changes in levels of small molecules that play important roles as intermediates in the tricarboxylic-acid and urea cycles, and amino-acid metabolism. Our findings point to widespread disruption of brain metabolism and indicate a complex phenotype beyond the gradient of neuropathologic damage observed in HD brain. (C) 2016 The Authors. Published by Elsevier B.V.
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