Conservation and divergence of myelin proteome and oligodendrocyte transcriptome profiles between humans and mice
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Evaluation Summary:
In this impressive manuscript the authors study the similarities and differences between the molecules that comprise the insulation that surrounds human brain nerve fibers (myelin), providing essential insight into how to interpret studies of myelin, from the perspective of different species. In all, this manuscript provides a new resource that will be of interest to the myelin community as well as investigators examining the contributions of oligodendrocytes to human neurodegenerative disease.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)
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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.
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Evaluation Summary:
In this impressive manuscript the authors study the similarities and differences between the molecules that comprise the insulation that surrounds human brain nerve fibers (myelin), providing essential insight into how to interpret studies of myelin, from the perspective of different species. In all, this manuscript provides a new resource that will be of interest to the myelin community as well as investigators examining the contributions of oligodendrocytes to human neurodegenerative disease.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)
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Reviewer #1 (Public Review):
In this Tools and Resources manuscript, Gargareta/Reuschenbach/Siems/Sun and colleagues use quantitative proteomics to analyze myelin from human white matter. This new dataset was rigorously generated - post-mortem variability was well-controlled, the unlabeled approach allowed for abundance analysis, and two runs further helped control for mass spec variability. Following the generation of this new human myelin proteome dataset, the authors compared it to their previously generated mouse myelin proteome dataset, and discovered a number of surprising species-specific results that were properly followed up in primary tissue, including the presence of previously thought to be PNS myelin specific protein PMP2 in human CNS myelin. Given that the myelin field predominately uses mouse models to study development …
Reviewer #1 (Public Review):
In this Tools and Resources manuscript, Gargareta/Reuschenbach/Siems/Sun and colleagues use quantitative proteomics to analyze myelin from human white matter. This new dataset was rigorously generated - post-mortem variability was well-controlled, the unlabeled approach allowed for abundance analysis, and two runs further helped control for mass spec variability. Following the generation of this new human myelin proteome dataset, the authors compared it to their previously generated mouse myelin proteome dataset, and discovered a number of surprising species-specific results that were properly followed up in primary tissue, including the presence of previously thought to be PNS myelin specific protein PMP2 in human CNS myelin. Given that the myelin field predominately uses mouse models to study development and disease/injury states, being aware of these key differences is critically important. The authors further compare their proteomics datasets to several existing transcriptomics datasets for both species, and find that these are well-correlated. In all, this is an excellent new resource for the myelin community as well as for anyone interested in how myelinating oligodendrocytes might contribute to human disease. The following are minor suggestions that the authors could consider:
• The text regarding Figure 3, Supplement 2 could have a more detailed description to underscore the significance of this data.
• Can the authors clarify brain region(s) in the text/methods beyond "white matter?"
• This resource would be of even greater utility to the community if there was any way to generate a searchable database, similar to https://www.brainrnaseq.org/. I realize there is a lot that goes into not only generating such a website but also maintaining it and that this may not be immediately possible.
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Reviewer #2 (Public Review):
This manuscript covers a worthy topic to understand mouse versus the human myelin proteome. These data have far reaching implications for translating studies in preclinical mouse models to humans. This study takes a deep dive into understanding differences between mouse and human myelin using both quantitative proteomics with comparison to published scRNA-seq datasets. Important comparisons are presented with relevant proteins known to drive myelin formation. Overall, this is a comprehensive study that will provide an important resource to the field.
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Reviewer #3 (Public Review):
In "Conservation and divergence of myelin proteome and oligodendrocyte transcriptome profiles between humans and mice" the authors profile the molecular composition of myelin in both humans and mice using mass spectrometry and complement this by analysing expression of mRNA in myelinating oligodendrocytes. The aim of the study is to investigate to what extent the molecular composition and general profile of myelin varies between species. To date, the mouse model has been the pre-dominant animal model for the study of myelin, an essentially vertebrate-specific feature that has allowed the evolution of large and complex nervous systems. Nonetheless, mice and humans diverged over 85 million years ago and it has remained unclear to what extent the molecular composition and in turn regulation of myelin and …
Reviewer #3 (Public Review):
In "Conservation and divergence of myelin proteome and oligodendrocyte transcriptome profiles between humans and mice" the authors profile the molecular composition of myelin in both humans and mice using mass spectrometry and complement this by analysing expression of mRNA in myelinating oligodendrocytes. The aim of the study is to investigate to what extent the molecular composition and general profile of myelin varies between species. To date, the mouse model has been the pre-dominant animal model for the study of myelin, an essentially vertebrate-specific feature that has allowed the evolution of large and complex nervous systems. Nonetheless, mice and humans diverged over 85 million years ago and it has remained unclear to what extent the molecular composition and in turn regulation of myelin and myelinating oligodendrocytes is similar or distinct between species. This study uses mass spectrometry to define the proteome of human myelin and compares these new data with previous profiling of myelin in mice. The very broad and deep analysis in the manuscript shows that the relative abundance of the small number of factors that comprise the majority of total myelin protein is very similar between mice and humans. In contrast, however, the study unmasks interesting differences in many less abundant proteins, with several found only in human myelin and others only in the mouse. The authors support these findings in follow-up studies that assess protein presence directly in tissue, and also by comparing the mRNA profile of human and mouse myelinating oligodendrocytes directly, finding that by and large the findings made at the protein level are predictable from their mRNA expression. This set of data will be enormously useful to the community, with a wealth of information available that is not feasible to convey in one manuscript narrative. It is also not feasible to assess the functional relevance of the species-specific aspects of mouse or human myelin in this initial study, but those will be very important avenues for future exploration. I expect this manuscript to greatly inform ongoing studies of myelin in both health and disease.
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