Probing the metabolic aberrations underlying mutant huntingtin toxicity in yeast and assessing their degree of preservation in humans and mice.
Metabolomics is a powerful multiparameter tool for evaluating phenotypic traits associated with disease processes. We have used (1)H NMR metabolome profiling to characterize metabolic aberrations in a yeast model of Huntington's disease that are attributable to the mutant huntingtin protein's gain-of-toxic-function effects. A group of 11 metabolites (alanine, acetate, galactose, glutamine, glycerol, histidine, proline, succinate, threonine, trehalose, and valine) exhibited significant concentration changes in yeast expressing the N-terminal fragment of a mutant human huntingtin gene. Correspondence analysis was used to compare results from our yeast model to data reported from transgenic mice expressing a mutant huntingtin gene fragment and Huntington's disease patients. This technique enabled us to identify a variety of both model-specific (pertaining to a single species) and conserved (observed in multiple species) biomarkers related to mutant huntingtin's toxicity. Among the 59 metabolites identified, four compounds (alanine, glutamine, glycerol, and valine) changed significantly in concentration in all three Huntington's disease systems. We propose that alanine, glutamine, glycerol, and valine should be considered as promising biomarkers for evaluating new Huntington's disease therapies, as well as for providing unique insight into the mechanisms associated with mutant huntingtin toxicity.
Joyner
P Matthew
PM
Natural Products Discovery Group, Department of Chemistry and Biochemistry, 620 Parrington Oval, Room 208, University of Oklahoma, Norman, Oklahoma 73019-3032, usa.
Matheke
Ronni M
RM
Smith
Lindsey M
LM
Cichewicz
Robert H
RH
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D050260:Carbohydrate Metabolism; D016009:Chi-Square Distribution; D005583:Fourier Analysis; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism*; D055442:Metabolome / Q000235:genetics*; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D025341:Principal Component Analysis; D012441:Saccharomyces cerevisiae / Q000235:genetics; D015398:Signal Transduction
D000596:Amino Acids; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins