Targeted biochemical profiling of brain from Huntington's disease patients reveals novel metabolic pathways of interest

Stewart F Graham, Xiaobei Pan, Ali Yilmaz, Shirin Macias, Andrew Robinson, David Mann, Brian D Green

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

Huntington's disease (HD) is a devastating, progressive neurodegenerative disease with a distinct phenotype characterized by chorea and dystonia, incoordination, cognitive decline and behavioral difficulties. The precise mechanisms of HD progression are poorly understood; however, it is known that there is an expansion of the trinucleotide cytosine-adenine-guanine (CAG) repeat in the Huntingtin gene. Herein DI/LC-MS/MS was used to accurately identify and quantify 185 metabolites in post mortem frontal lobe and striatum from HD patients and healthy control cases. The findings link changes in energy metabolism and phospholipid metabolism to HD pathology and also demonstrate significant reductions in neurotransmitters. Further investigation into the oxidation of fatty acids and phospholipid metabolism in pre-clinical models of HD are clearly warranted for the identification of potential therapies. Additionally, panels of 5 metabolite biomarkers were identified in both the frontal lobe (AUC = 0.962 (95% CI: 0.85-1.00) and striatum (AUC = 0.988 (95% CI: 0.899-1.00). This could have clinical utility in more accessible biomatrices such as blood serum for the early detection of those entering the prodromal phase of the disease, when treatment is believed to be most effective. Further evaluation of these biomarker panels in human cohorts is justified to determine their clinical efficacy.

Original languageEnglish
Pages (from-to)2430-2437
JournalBiochimica et biophysica acta
Early online date21 Apr 2018
DOIs
Publication statusPublished - 01 Jul 2018

Keywords

  • Journal Article

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