Preza, Elisavet;
(2020)
Stem cell models of C9orf72-linked Frontotemporal Dementia.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The GGGGCC repeat expansion in C9orf72 is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (ALS). Expanded repeat-associated toxicity from either RNA foci or dipeptide protein repeats (DPRs) as well as a loss of C9orf72 function due to haploinsufficiency, have all been described as potential pathogenic mechanisms in C9orf72-linked FTD/ALS (C9-FTD/ALS). Moreover, the C9orf72 protein has been suggested to play an important role in autophagy and lysosomal trafficking. The work presented in this thesis includes the investigation of FTD-related phenotypes and C9orf72 haploinsufficiency in C9orf72 patient iPSC-derived cortical neurons (iPSC-CNs), and the generation and study of C9orf72 knockout iPSC-CNs. C9orf72 patient iPSC-CNs exhibited: (i) sense RNA foci, (ii) poly-GP and poly-GR, (iii) C9orf72 promoter hypermethylation, (iv) reduction in C9orf72 total mRNA levels and (v) increased expression of intron1-retaining transcript, compared to control iPSC-CNs, with considerable variability between C9orf72 lines. No reduction in C9orf72 protein levels was detected in C9orf72 iPSC-CNs at 150 and 260 days in vitro. CRISPR/Cas9-mediated knockout of C9orf72 resulted in significant downregulation of autophagy-related genes ULK1, LC3B and LAMP1 in C9orf72-/- iPSC-CNs compared to isogenic C9orf72+/- and/or WT iPSC-CNs, indicative of altered basal autophagy. Moreover, preliminary findings suggest that induction of mitophagy is impaired in C9orf72-/- iPSC-CNs. Future work will be required to replicate this finding and further examine the potential role of C9orf72 in autophagy and mitophagy in iPSC-CNs and how its loss may contribute to C9-FTD/ALS.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Stem cell models of C9orf72-linked Frontotemporal Dementia |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/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 UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences 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 Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10116412 |
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