RNA signature of different lesion types in MS

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Unique RNA signature of different lesion types in the brain white matter in progressive multiple sclerosis

https://actaneurocomms.biomedcentral.co ... 019-0709-3

Conclusions

Our study is not without limitations. We used controls only without neurological disease. We did not separate rim and core in the chronic active and inactive lesions either. But the combination of different bioinformatics methods and validation by immunohistochemistry supported our conclusions, and such weakness does not hinder interpretation of changes in transcriptome signatures during lesion evolution and fate in the WM of progressive MS brain. Notable, the RNAscope validation on chronic active and remyelinating lesions from even the same patient confirmed that our results are not patient dependent but likely lesion dependent.

In conclusion, by next-generation RNA sequencing and a comprehensive computational systems medicine approach we identified mechanistic transcriptome signature of lesion evolution in the progressive MS brain WM. We found that the molecular signature of chronic active lesions was profoundly different from all other lesion types, and NAWM was more similar to control WM than to any other lesion types. It indicates that major gene expression changes occur both at early lesion genesis, and in lesions most characteristic as the late progressive phase develops.

The highly specific mechanistic signature of chronic active lesions indicates that as these lesions develop in progressive MS, molecular pathways are substantially altered: the unique mitochondrial/metabolic changes and specific downregulation of molecules involved in tissue repair indicate a stage of exhaustion. Besides unique sub-networks mechanistically different at lesions stages, some molecules were specifically regulated: CD26/DPP4 upregulation by microglia in the NAWM suggesting that a special microglia subset characterized by CD26 may play a role in early lesion development; CH3L1 in the chronic active rim by astrocytes; TGFβ transcripts and TGFβ-R2 expressed by astrocytes in remyelinating lesions in contrast to lesions with chronic active tissue damage. The uniqueness of lesion types also indicates that omics approaches should consider lesion stages, when expression and regulation of different molecules are addressed.

Although this study indicates the extreme diverse molecular events on transcriptome level at different lesion stages, yet our comprehensive unbiased search across subsets of multiple lesions provided a discovery of specific molecular mechanistic signatures validated by different approaches.