RNA Misprocessing in Neurodegeneration: Investigation of Novel RNA Targeting and Sequencing Approaches in Frontotemporal Dementia and Huntington’s Disease

This doctoral thesis explores the molecular mechanisms of RNA misprocessing in two major neurodegenerative diseases: Frontotemporal Dementia (FTD) and Huntington’s Disease (HD). The study focuses on the pathological consequences of mutations affecting RNA metabolism, particularly in the GRN gene associated with FTD and the HTT gene in HD.

The research provides a detailed molecular characterization of the GRN c.709-1G>A mutation, prevalent in individuals of Basque origin, which leads to defective splicing and reduced expression of the progranulin (PGRN) protein. The thesis evaluates different RNA-based therapeutic strategies—including CRISPR-dCasRx, modified U7 snRNAs, and antisense oligonucleotides (ASOs)—to correct the aberrant splicing patterns induced by this mutation.

In parallel, the thesis investigates cryptic polyadenylation events in the HTT gene using targeted 3’ end RNA sequencing (3’TRS) in cellular and mouse models, as well as human post-mortem samples. The results uncover novel polyadenylation patterns that may contribute to HD pathogenesis and could serve as new molecular biomarkers or therapeutic targets.

Overall, this work demonstrates the power of precise RNA targeting tools and high-throughput sequencing to elucidate the role of RNA misprocessing in neurodegeneration and paves the way for future RNA-based therapeutic developments.