Conservation and divergence of myelin proteome and oligodendrocyte transcriptome profiles between humans and mice

Elife. 2022 May 11;11:e77019. doi: 10.7554/eLife.77019.

Abstract

Human myelin disorders are commonly studied in mouse models. Since both clades evolutionarily diverged approximately 85 million years ago, it is critical to know to what extent the myelin protein composition has remained similar. Here, we use quantitative proteomics to analyze myelin purified from human white matter and find that the relative abundance of the structural myelin proteins PLP, MBP, CNP, and SEPTIN8 correlates well with that in C57Bl/6N mice. Conversely, multiple other proteins were identified exclusively or predominantly in human or mouse myelin. This is exemplified by peripheral myelin protein 2 (PMP2), which was specific to human central nervous system myelin, while tetraspanin-2 (TSPAN2) and connexin-29 (CX29/GJC3) were confined to mouse myelin. Assessing published scRNA-seq-datasets, human and mouse oligodendrocytes display well-correlating transcriptome profiles but divergent expression of distinct genes, including Pmp2, Tspan2, and Gjc3. A searchable web interface is accessible via www.mpinat.mpg.de/myelin. Species-dependent diversity of oligodendroglial mRNA expression and myelin protein composition can be informative when translating from mouse models to humans.

Keywords: Oligodendrocyte; axon-glia interaction; cross-species comparison; human; label-free proteomics; mouse; myelin sheath; neuroscience; scRNA-seq.

Plain language summary

Like the electrical wires in our homes, the processes of nerve cells – the axons, thin extensions that project from the cell bodies – need to be insulated to work effectively. This insulation takes the form of layers of a membrane called myelin, which is made of proteins and fats and produced by specialized cells called oligodendrocytes in the brain and the spinal cord. If this layer of insulation becomes damaged, the electrical impulses travelling along the nerves slow down, affecting the ability to walk, speak, see or think. This is the cause of several illnesses, including multiple sclerosis and a group of rare genetic diseases known as leukodystrophies. A lot of the research into myelin, oligodendrocytes and the diseases caused by myelin damage uses mice as an experimental model for humans. Using mice for this type of research is appropriate because of the ethical and technical limitations of experiments on humans. This approach can be highly effective because mice and humans share a large proportion of their genes. However, there are many obvious physical differences between the two species, making it important to determine whether the results of experiments performed in mice are applicable to humans. To do this, it is necessary to understand how myelin differs between these two species at the molecular level. Gargareta, Reuschenbach, Siems, Sun et al. approached this problem by studying the proteins found in myelin isolated from the brains of people who had passed away and donated their organs for scientific research. They used a technique called mass spectrometry, which identifies molecules based on their weight, to produce a list of proteins in human myelin that could then be compared to existing data from mouse myelin. This analysis showed that myelin is very similar in both species, but some proteins only appear in humans or in mice. Gargareta, Reuschenbach, Siems, Sun et al. then compared which genes are turned on in the oligodendrocytes making the myelin. The results of this comparison reflected most of the differences and similarities seen in the myelin proteins. Despite the similarities identified by Gargareta, Reuschenbach, Siems, Sun et al., it became evident that there are unexpected differences between the myelin of humans and mice that will need to be considered when applying results from mice research to humans. To enable this endeavor, Gargareta, Reuschenbach, Siems, Sun et al. have created a searchable web interface of the proteins in myelin and the genes expressed in oligodendrocytes in the two species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Connexins / metabolism
  • Humans
  • Mice
  • Mice, Inbred Strains
  • Myelin Proteins / genetics
  • Myelin Proteins / metabolism
  • Myelin Proteolipid Protein
  • Myelin Sheath* / genetics
  • Myelin Sheath* / metabolism
  • Nerve Tissue Proteins / metabolism
  • Oligodendroglia / metabolism
  • Proteome* / metabolism
  • Tetraspanins / genetics
  • Tetraspanins / metabolism
  • Transcriptome

Substances

  • Connexins
  • GJC3 protein, human
  • Myelin Proteins
  • Myelin Proteolipid Protein
  • Nerve Tissue Proteins
  • Proteome
  • Tetraspanins
  • Tspan2 protein, mouse

Associated data

  • GEO/GSE113973
  • GEO/GSE75330
  • GEO/GSE116470
  • GEO/GSE130119
  • GEO/GSE129788
  • GEO/GSE60361
  • GEO/GSE140511
  • GEO/GSE138852
  • GEO/GSE118257
  • GEO/GSE97930
  • SRA/SRP135960

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.