Cell type specific transcriptomic characterization of myelin abnormalities
von Ting Sun
Datum der mündl. Prüfung:2021-10-13
Erschienen:2022-08-22
Betreuer:Prof. Dr. Klaus-Armin Nave
Gutachter:Prof. Dr. Hannelore Ehrenreich
Gutachter:Prof.Dr. Michael Sereda
Zum Verlinken/Zitieren:
http://dx.doi.org/10.53846/goediss-9413
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Name:Sun_thesis.pdf
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Description:Thesis
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Zusammenfassung
Englisch
Myelin is indispensable for the fast and efficient transmission of electric signals along axons. The formation of myelin by oligodendrocytes in the central nervous system (CNS) is tightly regulated at the transcriptional level to achieve the required coordinated synthesis of myelin lipids and proteins. Disturbed oligodendroglial RNA profiles not only cause myelin abnormalities but also affect axon health and cause inflammation. Overlapping pathological features can be observed in other neurological disorders and in advanced brain aging. Together, this suggests that oligodendrocytes contribute to the onset and progression of CNS pathologies. However, to what degree oligodendrocytes and myelin abnormalities drive disease is unknown. Additionally, recent single-cell RNA sequencing (scRNA-seq) studies have revealed that oligodendrocytes are highly heterogeneous cells, which further increases the difficulty of defining the responsible oligodendroglial subpopulations and their corresponding signals. In the first project, in-house generated Plp1 -/y , Cnp -/- , and Foxg1-Cre Mbp fl/fl mutants were recruited for the single-cell resolution characterization of oligodendrocyte transcriptome changes induced by myelin deficiencies. Surprisingly, the absence of essential myelin genes led to a shift of the oligodendroglial transcriptional profiles towards distinct cellular states. However, such drastic subpopulation shifts did not result in catastrophic system failure but rather triggered mild responses in neurons, astrocytes, and microglia. Cell manifold modeling reconstructed mutant oligodendrocytes are caged at cell stages close to or within the range of physiological subpopulations. The project, therefore, discovered cell type- and subtype-specific transcription profiles of myelin mutant mice and the unexpected tight connectivities of oligodendrocyte molecular footprints in distinct myelin diseases. In the second project, we aimed to understand how oligodendrocytes and myelin defects contribute to neurodegenerative diseases by crossbreeding our myelin mutant mice to mouse models of Alzheimer’s disease (AD). Intriguingly, the mice with primary myelin dysfunctions showed elevated amyloid-beta (Aβ) plaque deposition. Mechanistically, myelin defects induced axonal swellings and likely enhanced local amyloid precursor protein (APP) processing. Moreover, by combining image analyses with scRNA-seq data, we inspected that microglia in myelin mutant mice are distracted from Aβ plaque removal, presumably due to the increasing engagement to myelin debris clearance. Conversely, in the absence of forebrain myelin, the deposition of Aβ plaques in AD models was delayed. Overall, my thesis provides a systematic characterization and crosswise comparison of transcriptomic changes in mutant oligodendrocytes and discusses potential downstream effects as a result of myelin dysfunctions. This work thus provides a novel model to assist our understanding of myelinating oligodendrocytes in health and disease.
Keywords: Myelin, Oligodendrocyte, Transcriptomics, Single-cell
