Poster 17: Metabolic Profiling in Non-Human Primate Model of Huntington's Disease Reveals Early Disruptions in Tryptophan Metabolism

Background Metabolomics is the systematic study of small molecule metabolites that are the end product of all forces, both endogenous and exogenous, that act upon a specific organism. Interactions among diet, environment, and genes, and their relative contribution to human health and disease, can be elucidated using metabolomics. Although rodent models of HD have been developed, these models do not satisfactorily parallel the brain changes and behavioral features observed in HD patients. Methods Hallmark features of HD, including nuclear inclusions and neuropil aggregates, were observed in the brains of transgenic monkeys expressing the huntingtin gene. Additionally, the transgenic monkeys showed important clinical features of HD, including dystonia and chorea. Taking advantage of new technology, we developed a method that uses a drop of blood processed with a simple extraction method to remove the proteins and injects directly onto a liquid chromatography–Fourier transform mass spectrometry (LC-FTMS) system. In 10 minutes, we are able to reliably detect 2500 metabolites. The method was applied to plasma from 2 HD monkeys (birth to 8 months) and wild-type controls. Results and Discussion Of the metabolites detected, 19 varied significantly between HD and wild type, 2 of which were important in tryptophan metabolism. These results confirm clinical research showing a disruption in tryptophan metabolism in HD patients. The 32 metabolites that changed most with time were compared with these 19 metabolites, and 2 unknown metabolites were found on both lists. Further investigation into the identity of these metabolites revealed one with a core indole group, suggesting an uncharacterized metabolite of tryptophan. Comparison of transgenic and wild-type monkeys showed putative biomarkers of early disease with relatively few animals. A pilot study is currently underway to test these results in humans and to suggest future therapeutic targets for drug development.