Transcriptomic studies of protein homeostasis perturbations in neurodegenerative disorders

Alzheimer’s Disease (AD) is the most common cause of dementia, but our understanding of its molecular origins is still incomplete. Genome-wide association studies (GWAS) have revealed key genes linked with the disease, but several more genes may need to be discovered to identify the broad range of biological processes underlying its onset and progression. To address this problem, based on the observed widespread transcriptional dysregulation closely associated with the pathology of AD, we developed novel methods and adapted published ones to provide a list of genes associated with Alzheimer’s disease. Subsequently this list can be used to identify key biological processes affected. Our approach involves two levels of granularity. Firstly, we identified a transcriptional fingerprint of the intrinsic vulnerability of healthy human brain tissues to Alzheimer’s disease. This was achieved by studying the gene expression patterns in brain regions involved in the staging of AD – the Braak regions of the brain. Secondly, we described how this fingerprint was differentially regulated at the mRNA level when comparing between brain tissues associated with healthy ageing and those associated with AD, by analysing the differences in the perturbations of its co-expression network. Our analysis was initially carried out on transcriptomic profiles of bulk tissue data, and was subsequently tailored to single-cell RNA sequencing datasets, in order to verify how working at different resolutions would affect our findings. Dimensionality reduction and clustering techniques were implemented to face the technical challenges of single-cell data. The analysis was then extended to a broader family of neurodegenerative disorders associated with the aggregation of tau protein, which is a hallmark of AD and other diseases, in order to underline the importance of the balance between key molecular mechanisms in combatting the disease progression. The endpoint of this work is a unified picture of the biological pathways that act as key drivers of Alzheimer’s disease.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2021

Author dc:creator

• Possenti, Andrea

Advisor dc:contributor.advisor

• Vendruscolo, Michele

• Transcriptomics
• Alzheimer's disease

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/04534779-4f81-4288-b979-697a22ea9769/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.72447

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/324993