Zanovello, Matteo; (2025) Elucidating TDP-43 Cryptic Exons and Short Tandem Repeat Expansions: Molecular Mechanisms and Epidemiological Insights in Neurodegenerative Disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

TDP-43 cytosolic aggregation and nuclear depletion occur in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and other neurodegenerative diseases, collectively called TDP-43 proteinopathies. Nuclear loss of TDP-43 causes the derepression of cryptic exons (CEs), often leading to transcript degradation through nonsense-mediated decay (NMD). While CEs play a pathogenic role in ALS/FTD, a thorough understanding of the biology of TDP-43 CEs and their relevance for other neurodegenerative diseases is still lacking. Short tandem repeat (STR) expansions are responsible for several neurodegenerative diseases, with some of them exhibiting TDP-43 pathology. Notwithstanding their role in neurodegeneration, their prevalence is unknown. In the first chapter, by leveraging novel bioinformatic tools on large whole-genome sequencing datasets, I uncover a surprisingly high occurrence of STR expansions in the general population and then estimate the prevalence and instability features of STR diseases by mathematical modelling. In the second chapter of this thesis, I characterise the biology of TDP-43 CEs by experimental and computational approaches. First, by inhibiting NMD, I demonstrate that while some CEs evade NMD and could serve as biomarkers, others are revealed only upon NMD inhibition. Later, I analyse how TDP-43 loss affects CE expression. I orthogonally validate these findings by iCLIP and postmortem RNA-sequencing. Sporadic inclusion body myositis (sIBM) is a muscle disease whose pathogenesis consists of inflammatory and degenerative features. In the third chapter, I examine the role of TDP-43 and its CEs in vivo by transcriptomics and proteomics analysis of sIBM biopsies, where TDP-43 aggregates in the skeletal muscle, linking CEs expression to adaptive immune responses. Overall, this work advances understanding of TDP-43 CE biology and identifies novel disease effectors and potential biomarkers for TDP-43 proteinopathies. Moreover, it sheds light on the prevalence of STR and related diseases, with important implications for genetic and clinical medicine.

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