Comparison of the Rat and Human Dorsal Root Ganglion Proteome

Adam G Schwaid,Alicja Krasowka-Zoladek,An Chi,Ivan Cornella-Taracido

doi:10.1038/s41598-018-31189-9

Adam G Schwaid, Alicja Krasowka-Zoladek + Show 2 more

Open Access

https://doi.org/10.1038/s41598-018-31189-9

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Abstract

Dorsal root ganglion (DRG) are a key tissue in the nervous system that have a role in neurological disease, particularly pain. Despite the importance of this tissue, the proteome of DRG is poorly understood, and it is unknown whether the proteome varies between organisms or different DRG along the spine. Therefore, we profiled the proteome of human and rat DRG. We identified 5,245 proteins in human DRG and 4959 proteins in rat DRG. Across species the proteome is largely conserved with some notable differences. While the most abundant proteins in both rat and human DRG played a role in extracellular functions and myelin sheeth, proteins detected only in humans mapped to roles in immune function whereas those detected only in rat mapped to roles in localization and transport. The DRG proteome between human T11 and L2 vertebrae was nearly identical indicating DRG from different vertebrae are representative of one another. Finally, we asked if this data could be used to enhance translatability by identifying mechanisms that modulate cellular phenotypes representative of pain in different species. Based on our data we tested and discovered that MAP4K4 inhibitor treatment increased neurite outgrowth in rat DRG as in human SH-SY5Y cells.

Highlights

A key factor in drug discovery success is translatability between preclinical models and human disease
We predicted and observed that treatment of rat Dorsal root ganglion (DRG) with a MAP4K4 inhibitor would increase neurite outgrowth, similar to effects observed in human SH-SY5Y cells
In order to understand the human DRG proteome we conducted in-depth shotgun proteomics on DRG tissue harvested from the T11 and L2 vertebrae of 4 human donors immediately post mortem

Summary

Introduction

A key factor in drug discovery success is translatability between preclinical models and human disease Without this ability progressing drug discovery programs is difficult as there is no practical way to test compounds or mechanisms in vivo prior to the clinic. Several papers have searched for proteins changing in rodent DRG between healthy and injured animals using 2D-gel electrophoresis coupled to mass spectrometry These studies expanded our undestanding of proteins involved in pain, but were only able to identify a small number of proteins[11,12]. We conducted proteomic studies in rat and human DRG in order to better navigate translation between these two systems. We predicted and observed that treatment of rat DRG with a MAP4K4 inhibitor would increase neurite outgrowth, similar to effects observed in human SH-SY5Y cells

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