Dimitriadis, Athanasios;
(2022)
Transcriptomics of prion diseases.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Despite substantial research aiming to elucidate prion disease pathogenesis, the underlying mechanisms of cellular toxicity and neurodegeneration remain poorly characterized. The human brain comprises numerous cell populations with a heterogeneous transcriptional landscape, complicating the interpretation of transcriptomic studies. To untangle this complexity, we first established and validated two single-nucleus sequencing methodologies and a bioinformatics pipeline for data analysis. We then designed a time-course case-control study of RML- and control brain homogenate-inoculated FVB mice (N = 95, time points: 20, 40, 80, 120 dpi and disease end-stage), and a human case-control study in post-mortem and biopsied brain samples (N = 26) and applied our transcriptomics pipeline. We generated 210,000 high-quality cell transcriptomes across 5 time points in mice and identified 26 subclusters of cortical neurons, interneurons, mature oligodendrocytes, oligodendrocyte precursor cells, vascular and leptomeningeal cells, and astrocytes. Glial activation was evident from 80 dpi, while our data suggested a selective transcriptomic response of individual cell clusters to disease. We identified a pattern of neuronal transcriptomic change shortly after RML-brain inoculation that quickly resolved, despite rapidly increasing prion titres in the brain, only to return at later stages when the neuropathology of prion disease was evident. Subsequent pathway analyses identified common perturbed biological pathways associated with synaptic dysfunction and ion homeostasis. Our human tissue samples did not pass quality control criteria, highlighting the need for different methodologies to assay archived samples. Here we provide the first single-cell transcriptomics study of prion diseases in mouse which found cell-type and time-specific patterns. Taken together, findings suggest that prion replication itself does not produce a transcriptomic signature in the brain, rather, a transient pattern of toxicity can be seen immediately following inoculation of prion disease brain homogenate, which becomes re-established as prion disease neuropathology develops.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Transcriptomics of prion diseases |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10155944 |
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