title: Identification of elevated urea as a severe, ubiquitous metabolic defect in the brain of patients with Huntington's disease.
abstract: Huntington's disease (HD) is a neurodegenerative disorder wherein the aetiological defect is a mutation in the Huntington's gene (HTT), which alters the structure of the huntingtin protein through the lengthening of a polyglutamine tract and initiates a cascade that ultimately leads to dementia and premature death. However, neurodegeneration typically manifests in HD only in middle age, and processes linking the causative mutation to brain disease are poorly understood. Here, our objective was to elucidate further the processes that cause neurodegeneration in HD, by measuring levels of metabolites in brain regions known to undergo varying degrees of damage. We applied gas-chromatography/mass spectrometry-based metabolomics in a case-control study of eleven brain regions in short post-mortem-delay human tissue from nine well-characterized HD patients and nine controls. Unexpectedly, a single major abnormality was evident in all eleven brain regions studied across the forebrain, midbrain and hindbrain, namely marked elevation of urea, a metabolite formed in the urea cycle by arginase-mediated cleavage of arginine. Urea cycle activity localizes primarily in the liver, where it functions to incorporate protein-derived amine-nitrogen into urea for recycling or urinary excretion. It also occurs in other cell-types, but systemic over-production of urea is not known in HD. These findings are consistent with impaired local urea regulation in brain, by up-regulation of synthesis and/or defective clearance. We hypothesize that defective brain urea metabolism could play a substantive role in the pathogenesis of neurodegeneration, perhaps via defects in osmoregulation or nitrogen metabolism. Brain urea metabolism is therefore a target for generating novel monitoring/imaging strategies and/or therapeutic interventions aimed at ameliorating the impact of HD in patients.
authors.affiliation: School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand; Centre for Brain Research and Department of Anatomy with Radiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK; Institute of Human Development, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, UK.
authors.forename: Stefano
authors.initials: S
authors.lastname: Patassini
authors.affiliation: Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Begley
authors.affiliation: School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand.
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Reid
authors.affiliation: School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand; Centre for Brain Research and Department of Anatomy with Radiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK; Institute of Human Development, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, UK; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
authors.forename: Jingshu
authors.initials: J
authors.lastname: Xu
authors.affiliation: Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Church
authors.affiliation: Centre for Brain Research and Department of Anatomy with Radiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Maurice
authors.initials: M
authors.lastname: Curtis
authors.affiliation: Centre for Brain Research and Department of Anatomy with Radiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Mike
authors.initials: M
authors.lastname: Dragunow
authors.affiliation: Centre for Brain Research and Department of Anatomy with Radiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Waldvogel
authors.affiliation: Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK; Institute of Human Development, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, UK.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Unwin
authors.affiliation: School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand; Centre for Brain Research and Department of Anatomy with Radiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Russell G
authors.initials: RG
authors.lastname: Snell
authors.affiliation: Centre for Brain Research and Department of Anatomy with Radiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Richard L M
authors.initials: RL
authors.lastname: Faull
authors.affiliation: School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand; Centre for Brain Research and Department of Anatomy with Radiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK; Institute of Human Development, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, UK; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand. Electronic address: garth.cooper@manchester.ac.uk.
authors.forename: Garth J S
authors.initials: GJ
authors.lastname: Cooper
mesh_terms: D000368:Aged; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D014508:Urea / Q000032:analysis / Q000378:metabolism*
chemical_list: D014508:Urea
keywords: Brain urea; GC MS; Human brain; Huntington's disease; Metabolic brain disease; Neurodegenerative disease