Gabriele, Rebecca Maria Cecilia;
(2021)
Investigating the function of the Alzheimer’s disease risk gene BIN1 and its role in Alzheimer’s disease.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Bridging integrator 1 (BIN1) is a major risk factor for Alzheimer’s disease (AD). BIN1 is enriched in the brain, where it is found in neurons and glial cells in the brain, with each cell type expressing specific isoforms. Interestingly, previous studies have shown that BIN1 expression is altered in AD brains. However, little is known on how each isoform is affected and how BIN1 contributes to AD pathogenesis. Most AD-related BIN1 risk variants lie in the 5’ region of the gene, suggesting that altered BIN1 expression could be the genetic mechanism contributing to increased AD risk. Chapuis et al. (2013) have identified a risk variant rs59335482, a 3 base pair (bp) insertion upstream of the BIN1 promoter, associated with global BIN1 transcript level increase. However, whether the 3 bp insertion directly affects BIN1 expression and whether it affects all BIN1 isoforms has never been investigated before. We generated an in vitro iPSC model carrying the 3 bp insertion using CRISPR/Cas9 technology and investigated how it affects BIN1 isoform expression. Our results indicated that the 3 bp insertion increased the expression of longer BIN1 isoforms containing exon 7 in iPSC-derived neurons. Moreover, the subcellular localisation of BIN1 in primary rat cortical neurons indicated BIN1 co-localises with the endoplasmic reticulum (ER), suggesting BIN1 could potentially play a role in ER-related biological processes. Our data showed that altered levels of the neuronal isoforms of BIN1 could modulate the unfolded protein response (UPR), an ER-stress triggered mechanism, by affecting ATF6 activation. Interestingly, the UPR is thought to play a role in AD pathogenesis. Altogether, the results of this study addressed some of the unanswered questions about BIN1 transcript expression in AD and shed light on possible mechanisms affected by altered BIN1 expression.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Investigating the function of the Alzheimer’s disease risk gene BIN1 and its role in Alzheimer’s disease |
| Event: | UCL (University College London) |
| 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 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/10135738 |
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