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

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 CNS 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. Species-dependent diversity of oligodendroglial mRNA-expression and myelin protein composition can be informative when translating from mouse models to humans.

Marked regional glial heterogeneity in the human white matter of the central nervous system

“…However, newly formed oligodendrocytes are absent from the human dataset and the SPARC -positive, RBFOX1 -negative human cluster Oligo_F is missing in the mouse datasets, even in the adult mouse spinal cord samples, suggesting it may be human-specific (2g,h). There are proteomic differences between human and murine CNS myelin including the human-specific expression of Peripheral Myelin Protein 2 ( PMP2 ) 41 , which is highly expressed in Oligo_F and therefore may contribute to this observed proteomic species differences. More intermediate cells between the state of OPCs and oligodendrocytes were found in the mouse data, particularly in the juvenile data (2g,h), consistent with our data suggesting that human adult normal CNS cells are not actively differentiating.…”

CNS myelination requires VAMP2/3-mediated membrane expansion in oligodendrocytes

“…6b, Supplementary Table 5). 98% of the VAMP2/3-dependent hits had also been detected in acutely isolated oligodendrocytes from mouse brains and from purified myelin, validating the ability of primary culture to recapitulate in vivo oligodendrocytes 24,50,51 . Gene ontology analysis revealed a significant enrichment of proteins that localize to myelin sheaths, paranodes, cell-cell junctions, and vesicles (Fig.…”

CMTM5 - a novel CNS myelin protein involved in preserving axonal integrity

“…Further, CMTM5 is expressed by oligodendrocytes of mice and humans (Figure 3C, F) (Jäkel et al, 2019;Zhou et al, 2020) and was also mass-spectrometrically identified in purified CNS myelin before (Jahn et al, 2020). Additionally, we identified CMTM5 in myelin derived from wildtype mice and non-diseased humans (Fig 3G) and found the abundance to be roughly equal between the two species (Gargareta et al, 2022). (Zhang et al, 2014).…”

“…From all the members of the CMTM protein family only CMTM5 is expressed in myelinating oligodendrocytes to a considerable amount (Figure 3A, B). Further, the expression of CMTM5 is mostly specific for cells of the oligodendrocyte lineage in humans and mice (Figure 3C-F) and was identified in datasets analyzing myelin (Gargareta et al, 2022;Jahn et al, 2020) of both species. To date, CMTM5 has never been described as a CNS myelin protein and its function in oligodendrocytes has not been investigated until now.…”

“…Abundance of CMTM5 is relatively similar in both species. Data from (Gargareta et al, 2022). (H) Structure prediction of CMTM5 in mice according to AlphaFold2 (Jumper et al, 2021).…”