Brain Advance Access originally published online on February 7, 2006
Brain 2006 129(4):877-886; doi:10.1093/brain/awl027
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Huntington disease patients and transgenic mice have similar pro-catabolic serum metabolite profiles
1 Department of Medical Genetics, Cambridge Institute for Medical Research, 2 Department of Medicine, University of Cambridge, Addenbrooke's Hospital, 3 Cambridge Centre for Brain Repair, Forvie Site, Robinson Way, 4 Translational Research Unit, Papworth Hospital NHS Trust, Papworth Everard, Cambridge, 5 Suffolk Mental Health Partnership NHS Trust, Department of Psychiatry, Wedgwood House, West Suffolk Hospital, Bury St Edmunds and 6 School of Chemistry, University of Manchester, Manchester, UK
Correspondence to: Prof. David C. Rubinsztein, MB, ChB, PhD, Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2XY, UK E-mail: dcr1000{at}hermes.cam.ac.uk
There has been considerable progress recently towards developing therapeutic strategies for Huntington's disease (HD), with several compounds showing beneficial effects in transgenic mouse models. However, human trials in HD are difficult, costly and time-consuming due to the slow disease course, insidious onset and patient-to-patient variability. Identification of molecular biomarkers associated with disease progression will aid the development of effective therapies by allowing further validation of animal models and by providing hopefully more sensitive measures of disease progression. Here, we apply metabolic profiling by gas chromatography-time-of-flight-mass spectrometry to serum samples from human HD patients and a transgenic mouse model in a hypothesis-generating search for disease biomarkers. We observed clear differences in metabolic profiles between transgenic mice and wild-type littermates, with a trend for similar differences in human patients and control subjects. Thus, the metabolites responsible for distinguishing transgenic mice also comprised a metabolic signature tentatively associated with the human disease. The candidate biomarkers composing this HD-associated metabolic signature in mouse and humans are indicative of a change to a pro-catabolic phenotype in early HD preceding symptom onset, with changes in various markers of fatty acid breakdown (including glycerol and malonate) and also in certain aliphatic amino acids. Our data raise the prospect of a robust molecular definition of progression of HD prior to symptom onset, and if validated in a genuinely prospective fashion these biomarker trajectories could facilitate the development of useful therapies for this disease.
Key Words: Huntington's disease; polyglutamine; metabonomics; metabolomics; biomarker
Abbreviations: HD = Huntington's disease; GC-TOF-MS = gas chromatography-time-of-flight-mass spectrometry; PCA = principal components analysis; PC-DFA = principal components discriminant function analysis; PLS-DA = projection to latent structures discriminant analysis; UHDRS = unified Huntington's disease rating scale
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Received November 14, 2005. Revised January 4, 2006. Accepted January 5, 2006.
* These authors contributed equally to the study.
The study has four equal senior authors.
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