Unraveling the impact of RNA-editing in neurodegeneration: a focus on TDP-43 related frontotemporal dementia.

Age-related neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD), are a major public health problem since there is no effective treatment due to the poor understanding of the pathological processes involved in neuronal death. RNA editing, particularly A-to-I changes mediated by ADAR enzymes, stands as the most prevalent form of post-transcriptional RNA modification. Emerging evidence indicates that the efficiency and pattern of RNA editing in the brain are dynamically regulated during aging and can potentially lead to some neurodegenerative diseases. Despite recent advances in the topic, much remains unknown about how ADAR enzymes regulate RNA-editing and how A to I changes are involved in the onset and development of TDP43 proteinopathies such as ALS and FTD. In ALS, previous studies have described that nuclear clearance of TDP-43 leads to ADAR2 dysregulation and downstream changes in motor neuron RNA editome. However, these results are questioned in other studies using different approaches. Moreover, the function and regulation of RNA editing have not yet been studied in FTD. To address this critical knowledge gap, I will characterize ADAR expression and processing, their protein regulatory network and localization on brain tissue and iPSC-derived from FTD patients and controls. Then, I will describe the resultant RNA editome by applying direct long-read Oxford Nanopore and Illumina RNA-sequencing technologies, coupled with new cutting-edge bioinformatics pipelines. Finally, after identifying the disease-modifying A-to-I events of interest, I will employ antisense RNA strategies to manipulate specific RNA-editing patterns to investigate their function and therapeutic potential in FTD-TDP43. Overall, NeuroEDIT will generate fundamental knowledge to understand the role of RNA editing in neurodegeneration which may result in novel therapeutic targets based on RNA technology.