Metabolomics: An Emerging "Omics" Platform for Systems Biology and Its Implications for Huntington Disease Research

Abstract

Huntington's disease (HD) is a progressive, fatal neurodegenerative disease characterized by motor, cognitive, and psychiatric symptoms. 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. Important new strategies are of paramount importance to identify early biomarkers with predictive value for intervening in disease progression at a stage when cellular dysfunction has not progressed irreversibly. Metabolomics is the study of global metabolite profiles in a system (cell, tissue, or organism) under certain conditions and is becoming an essential tool for the systemic characterization of metabolites to provide a snapshot of the functional and pathophysiological states of an organism and support disease diagnosis and biomarker discovery. This review briefly highlights the historical progress of metabolomic methodologies, followed by a more detailed review of the use of metabolomics in HD research to enable a greater understanding of the pathogenesis, its early prediction, and finally the main technical platforms in the field of metabolomics.

Keywords: Huntington disease; NMR; biomarker discovery; mass spectrometry; metabolomics.

Figure 4

A schematic diagram of how an NMR instrument works and how spectra are produced. (i) Representation of nuclei without and within a magnetic field [138]. (ii) The spectra are produced through magnetic resonance frequency [138]. (iii) Initial signal received from NMR analysis prior to Fourier transformation (FT); 2-week-old plant material. (iv) The spectrum produced after FT. The ¹H-NMR spectrum corresponds to the free induction decay (FID) file used to produce panel (iii). (v) ¹H-NMR spectrum of Drosophila melanogaster metabolites [139].

Figure 1

The Medieval urine wheel was used for diagnosing the diseases according to the colour, smell, and taste of the patient’s urine. The medieval wheel complements modern metabolomic research, as many diseases affect metabolism and many changes in metabolism can be detected in the urine. The urine wheel was published in 1506 by Ullrich Pindar, in his book Epiphanie Medicorum. The figure was adapted from Nicholson 2 [22].

Figure 2

Histogram of the published manuscripts on Huntington’s disease. The chart is derived from the PubMed search engine by using the keyword “Huntington’s Disease.” The csv file format was obtained in June 2021 to plot an individual histogram of each decade. (i) Huntington’s research has continued to increase over the past two decades. (ii) The number of published manuscripts increased recently compared to early 1900 to 2000.

Figure 3

An overview of multi-omics analysis. Omics provide paramount view of biological cascade [1]. The diagram describes the advantage and disadvantage of omics analysis.

Figure 5

Schematic diagram of how mass spectrometry works. (i) Principal components of a mass spectrometer. (ii) How formation of ions occurs during the most used electrospray soft ionization [178]. (iii) Detection mechanism in time-of-fight, ion trap both quadrupole and orbitrap and triple quadrupole. (iv) A mass spectrum of plasma metabolites obtained by direct infusion of a sample into electrospray ionization coupled with quadrupole time-of-flight mass spectrometry [179].

Figure 6

Schematic diagram of how omics platforms are used for potential biomarker discovery. The workflow is based on the LC/MS platform.

Figure 7

Difference between targeted and untargeted analysis. Untargeted approach employs analysis of all metabolites detected by mass spectrometer, whereas targeted approach only focuses on known metabolites [121,207].