title: Metabolic profiling of presymptomatic Huntington's disease sheep reveals novel biomarkers.
abstract: The pronounced cachexia (unexplained wasting) seen in Huntington's disease (HD) patients suggests that metabolic dysregulation plays a role in HD pathogenesis, although evidence of metabolic abnormalities in HD patients is inconsistent. We performed metabolic profiling of plasma from presymptomatic HD transgenic and control sheep. Metabolites were quantified in sequential plasma samples taken over a 25 h period using a targeted LC/MS metabolomics approach. Significant changes with respect to genotype were observed in 89/130 identified metabolites, including sphingolipids, biogenic amines, amino acids and urea. Citrulline and arginine increased significantly in HD compared to control sheep. Ten other amino acids decreased in presymptomatic HD sheep, including branched chain amino acids (isoleucine, leucine and valine) that have been identified previously as potential biomarkers of HD. Significant increases in urea, arginine, citrulline, asymmetric and symmetric dimethylarginine, alongside decreases in sphingolipids, indicate that both the urea cycle and nitric oxide pathways are dysregulated at early stages in HD. Logistic prediction modelling identified a set of 8 biomarkers that can identify 80% of the presymptomatic HD sheep as transgenic, with 90% confidence. This level of sensitivity, using minimally invasive methods, offers novel opportunities for monitoring disease progression in HD patients.
authors.affiliation: Chronobiology, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, United Kingdom.
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Skene
authors.affiliation: Chronobiology, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, United Kingdom.
authors.forename: Benita
authors.initials: B
authors.lastname: Middleton
authors.affiliation: Preclinical, Imaging &Research Laboratories (PIRL), SAHMRI, Gilles Plains, Adelaide, Australia.
authors.forename: Cara K
authors.initials: CK
authors.lastname: Fraser
authors.affiliation: National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands.
authors.forename: Jeroen L A
authors.initials: JL
authors.lastname: Pennings
authors.affiliation: Preclinical, Imaging &Research Laboratories (PIRL), SAHMRI, Gilles Plains, Adelaide, Australia.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Kuchel
authors.affiliation: South Australian Research and Development Institute, Roseworthy, South Australia.
authors.forename: Skye R
authors.initials: SR
authors.lastname: Rudiger
authors.affiliation: South Australian Research and Development Institute, Roseworthy, South Australia.
authors.forename: C Simon
authors.initials: CS
authors.lastname: Bawden
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, United Kingdom.
authors.forename: A Jennifer
authors.initials: AJ
authors.lastname: Morton
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics; D019540:Area Under Curve; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism*; D002956:Citrulline / Q000378:metabolism; D005838:Genotype; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology* / Q000662:veterinary; D016015:Logistic Models; D055432:Metabolomics; D012372:ROC Curve; D012756:Sheep
chemical_list: D000597:Amino Acids, Branched-Chain; D015415:Biomarkers; D002956:Citrulline; C024917:symmetric dimethylarginine; C018524:N,N-dimethylarginine; D001120:Arginine