Identification of elevated urea as a severe, ubiquitous metabolic defect in the brain of patients with Huntington's disease

Stefano Patassini, Paul Begley, Suzanne J Reid, Jingshu Xu, Stephanie J Church, Maurice Curtis, Mike Dragunow, Henry J Waldvogel, Richard D Unwin, Russell G Snell, Richard L M Faull, Garth Cooper

    Research output: Contribution to journalArticlepeer-review


    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.

    Original languageEnglish
    Pages (from-to)161-6
    Number of pages6
    JournalBiochemical and biophysical research communications
    Issue number1-2
    Publication statusPublished - 3 Nov 2015


    • Aged
    • Brain
    • Case-Control Studies
    • Female
    • Gas Chromatography-Mass Spectrometry
    • Humans
    • Huntington Disease
    • Male
    • Middle Aged
    • Urea


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