Metabolic signatures of Huntington's disease (HD): (1)H NMR analysis of the polar metabolome in post-mortem human brain.
Huntington's disease (HD) is an autosomal neurodegenerative disorder affecting approximately 5-10 persons per 100,000 worldwide. The pathophysiology of HD is not fully understood but the age of onset is known to be highly dependent on the number of CAG triplet repeats in the huntingtin gene. Using (1)H NMR spectroscopy this study biochemically profiled 39 brain metabolites in post-mortem striatum (n=14) and frontal lobe (n=14) from HD sufferers and controls (n=28). Striatum metabolites were more perturbed with 15 significantly affected in HD cases, compared with only 4 in frontal lobe (p<0.05; q<0.3). The metabolite which changed most overall was urea which decreased 3.25-fold in striatum (p<0.01). Four metabolites were consistently affected in both brain regions. These included the neurotransmitter precursors tyrosine and l-phenylalanine which were significantly depleted by 1.55-1.58-fold and 1.48-1.54-fold in striatum and frontal lobe, respectively (p=0.02-0.03). They also included l-leucine which was reduced 1.54-1.69-fold (p=0.04-0.09) and myo-inositol which was increased 1.26-1.37-fold (p<0.01). Logistic regression analyses performed with MetaboAnalyst demonstrated that data obtained from striatum produced models which were profoundly more sensitive and specific than those produced from frontal lobe. The brain metabolite changes uncovered in this first (1)H NMR investigation of human HD offer new insights into the disease pathophysiology. Further investigations of striatal metabolite disturbances are clearly warranted.
Beaumont Research Institute, Beaumont Health, 3811 W. 13 Mile Road, Royal Oak, MI 48073, United States. Electronic address: stewart.graham@beaumont.edu.
Stewart F
SF
Graham
Beaumont Research Institute, Beaumont Health, 3811 W. 13 Mile Road, Royal Oak, MI 48073, United States.
Praveen K
PK
Kumar
Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada; Department of Computing Science, University of Alberta, Edmonton, AB, Canada.
Trent
T
Bjorndahl
Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada; Department of Computing Science, University of Alberta, Edmonton, AB, Canada.
BeomSoo
B
Han
Beaumont Research Institute, Beaumont Health, 3811 W. 13 Mile Road, Royal Oak, MI 48073, United States.
Ali
A
Yilmaz
University of Michigan, Ann Arbour, MI, United States.
Eric
E
Sherman
Beaumont Research Institute, Beaumont Health, 3811 W. 13 Mile Road, Royal Oak, MI 48073, United States.
Ray O
RO
Bahado-Singh
Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada; Department of Computing Science, University of Alberta, Edmonton, AB, Canada.
David
D
Wishart
Institute of Brain Behavior and Mental Health, University of Manchester, UK.
David
D
Mann
Advanced Asset Technology Centre, Institute for Global Food Security, Queen's University Belfast, Stranmillis Road, Belfast BT9 5AG, UK.
Brian D
BD
Green
D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D003342:Corpus Striatum / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism*; D007294:Inositol / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D053858:Metabolic Networks and Pathways; D055442:Metabolome
D007294:Inositol; D007930:Leucine
(1)H NMR; Brain; Huntington's disease; Metabolites; Metabolomics