| dc.contributor.advisor | Nave, Klaus-Armin Prof. Dr. | |
| dc.contributor.author | Sun, Ting | |
| dc.date.accessioned | 2022-08-22T09:23:11Z | |
| dc.date.available | 2022-10-12T00:50:12Z | |
| dc.date.issued | 2022-08-22 | |
| dc.identifier.uri | http://resolver.sub.uni-goettingen.de/purl?ediss-11858/14217 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-9413 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | Cell type specific transcriptomic characterization of myelin abnormalities | de |
| dc.type | cumulativeThesis | de |
| dc.contributor.referee | Ehrenreich, Hannelore Prof. Dr. | |
| dc.date.examination | 2021-10-13 | de |
| dc.description.abstracteng | 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. | de |
| dc.contributor.coReferee | Sereda, Michael Prof.Dr. | |
| dc.subject.eng | Myelin, Oligodendrocyte, Transcriptomics, Single-cell | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-ediss-14217-2 | |
| dc.affiliation.institute | Biologische Fakultät für Biologie und Psychologie | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.description.embargoed | 2022-10-12 | de |
| dc.identifier.ppn | 1815060867 | |
| dc.identifier.orcid | https://orcid.org/0000-0002-7104-7215 | de |
| dc.notes.confirmationsent | Confirmation sent 2022-08-22T09:45:01 | de |