Brown, Anna Leigh; (2024) TDP-43-mediated splicing control and RNA stability: unveiling mechanisms and disease implications in ALS and FTD. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

TAR DNA-binding protein 43 (TDP-43) TDP-43 is an RNA-binding protein whose cytosolic aggregation and nuclear depletion is linked to amyotrophic lateral sclerosis (ALS), fronto-temporal dementia (FTD), and found in 60% of Alzheimer's cases. TDP-43 controls RNA functions like splicing and stability. In disease, TDP-43 dysfunction causes cryptic splicing, where intronic sequences are incorporated into mature RNA. Though cryptic splicing signifies TDP-43 dysfunction post-mortem, the full extent of TDP-43’s cryptic splicing targets, and how these cryptic splicing events affect disease progression is unknown. This thesis performed a comprehensive analysis of TDP-43 regulated cryptic events in neuronal cell lines and in human post-mortem tissue, as well as providing the first ever transcriptome wide study of RNA stability after TDP-43 depletion in human neurons. I created reproducible analysis pipelines to perform splicing analyses and used these pipelines to uncover thousands of TDP-43 regulated cryptic splicing events in human neuronal cell lines. Furthermore, I revealed a profound RNA destabilising effect of TDP-43 depletion using the metabolic labelling technique SLAM- sequencing. Through analysis of the largest RNA-sequencing database of ALS/FTD tissue, the New York Genome Consortium ALS/FTD dataset, I revealed potential TDP-43 disease effectors and biomarkers of TDP-43 proteinopathy. Finally, I played a role in discovering the molecular mechanisms underlying the ALS/FTD risk SNPs in the UNC13A gene.

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