Metabolite mapping reveals severe widespread perturbation of multiple metabolic processes in Huntington's disease human brain.
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.
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. Electronic address: stefano.patassini-2@manchester.ac.uk.
Stefano
S
Patassini
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.
Paul
P
Begley
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.
Jingshu
J
Xu
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.
Stephanie J
SJ
Church
School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand.
Suzanne J
SJ
Reid
Centre for Brain Research and Department of Anatomy with Radiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, United States.
Eric H
EH
Kim
Centre for Brain Research and Department of Anatomy with Radiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Maurice A
MA
Curtis
Centre for Brain Research and Department of Anatomy with Radiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Mike
M
Dragunow
Centre for Brain Research and Department of Anatomy with Radiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Henry J
HJ
Waldvogel
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.
Russell G
RG
Snell
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.
Richard D
RD
Unwin
Centre for Brain Research and Department of Anatomy with Radiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Richard L M
RL
Faull
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.
Garth J S
GJ
Cooper
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; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D055432:Metabolomics; D008875:Middle Aged; D014018:Tissue Distribution
Brain urea metabolism; Huntington's disease; Inositol pathway; Metabolic brain disease; Neurodegenerative disease; Polyol pathway