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Molecular Physiome of Brain Regions Identified Using Top-Down Proteomics and MALDI Imaging Mass Spectrometry

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MALDI imaging mass spectrometry (MALDI-IMS) is the use of matrix-assisted laser desorption ionization as a mass spectrometry imaging technique. It enables the analysis of large amounts of molecules within a tissue without causing tissue destruction.

A group from the University of Lille have combined MALDI-IMS with top-down proteomics to characterise the molecular physiome of rat brain regions.

Led by Michel Salzet and Isabelle Fournie, the team developed the novel strategy combining MALDI-IMS and spatially-resolved top-down proteomics to investigate differences in protein expression at the cellular level.

First, molecular histology was performed using MALDI-IMS and spatial segmentation to distinguish Regions of Interest (ROIs) within a tissue. These ROIs were then subjected to protein microextraction and analysed.

On-tissue spatially-resolved proteomics provided a direct means to examine proteomic fluctuations at the level of the cells in response to changes in the tissue microenvironment. Combining this technique with MALDI-IMS, which can map the distribution of molecules, enabled spatial quantification of proteins at the microscale level. Enabling correlation of shot-gun proteomics and protein quantification with expression changes and cellular physiology.

The group investigated 3 brain regions, the corpus callosum, hippocampus and medulla oblongata, leading to the characterization of 123 reference proteins. Moreover, they identified 8 alternative proteins produced from alternative open reading frames (AltORF). They also found that some proteins displayed specific post-translational modification profiles or truncation linked to the brain regions and their functions.

Systems biology analysis performed on the proteome identified in each region allowed the scientists to associate sub-networks with the functional physiology of each brain region.

As an example, mapping of the distribution of the matrix metallopeptidase 3-cleaved C-terminal fragment of α-synuclein (aa 95–140) identified its specific distribution along the hippocampal dentate gyrus.

Taken together, the group established the molecular physiome of 3 rat brain regions through reference and hidden proteome characterization.

The group say that this novel combination can be used to search for biomarkers, detect post transcriptional modifications and identify novel proteins expressed from alternative open reading frames.

Delcourt, V., Franck, J., Quanico, J., Gimeno, J. P., Wisztorski, M., Raffo-Romero, A., ... & Fournier, I. (2018). Spatially-Resolved Top-down Proteomics Bridged to MALDI MS Imaging Reveals the Molecular Physiome of Brain Regions. Molecular & Cellular Proteomics, 17(2), 357-372.