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Review
. 2021;10(2):239-257.
doi: 10.3233/JHD-200465.

Taming the Huntington's Disease Proteome: What Have We Learned?

Connor Seeley  1 , Kimberly B Kegel-Gleason  1
Affiliations
Review

Taming the Huntington's Disease Proteome: What Have We Learned?

Connor Seeley et al. J Huntingtons Dis. 2021.

Abstract

Mass spectrometry (MS) is a physical technique used to identify specific chemicals and molecules by precise analysis of their mass and charge; this technology has been adapted for biological sciences applications. Investigators have used MS to identify differential expressions of proteins in Huntington's disease (HD), to discover Huntingtin (HTT) interacting proteins and to analyze HTT proteoforms. Using systems biology and computational approaches, data from MS screens have been leveraged to find differentially expressed pathways. This review summarizes the data from most of the MS studies done in the HD field in the last 20 years and compares it to the protein data reported before the use of MS technology. The MS results validate early findings in the field such as differential expression of PDE10a and DARPP-32 and identify new changes. We offer a perspective on the MS approach in HD, particularly for identification of disease pathways, the challenges in interpreting data across different studies, and its application to protein studies moving forward.

Keywords: HTT; Huntingtin; Huntington’s disease; interactome; mass spectrometry; proteome; proteomics.

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Conflict of interest statement

KKG spouse owns individual stock in the following companies: Bristol-Myers Squibb Company, Cisco Systems, Inc., GE Healthcare Life Sciences, Generex Biotechnology Corporation, GlaxoSmithKline, Metabolix Bioplastics, Nanogen, Inc., Repligen Corporation. CS has no conflict of interest to report.

Figures

Fig. 1
Fig. 1
Determining peptide composition using mass references values. This graph shows an example mass spectrum with intensity graphed on the y-axis and Mass/Charge (m/z) ratio graphed on the x-axis. In this case the first 3 amino acids of the HTT protein, methionine, alanine, and threonine are deducted from the graph by determining the change in mass between each peak and referring to Table 1. Charted here is the first three amino acids of the HTT peptide (MATLEKLMKA . . .).
Fig. 2
Fig. 2
A) Crude schematic of a MALDI TOF MS set up with the three essential components; Ion source, mass analyzer (electric or magnetic field) and a detector. For MALDI the sample is on a solid support. B) Crude schematic of the Ionization chamber of an ESI mass spectrometer. The sample enters the chamber as a liquid through a capillary. The sample is then aerosolized by the high voltage. Note the charge can be manipulated to select for either positive or negatively charged ions which are sent to mass analyzer and detector as in A.
Fig. 3
Fig. 3
General workflow for mass spectrometry analysis of proteins.
See this image and copyright information in PMC

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