Seminar

Investigation of RNA-misprocessing in neurological diseases for the development of novel diagnostic and therapeutic approaches.

Lorea Blázquez

RNA-processing is the molecular mechanism by which precursor messenger RNAs (pre-mRNAs) are capped, spliced and polyadenylated. It is a fundamental process that ensures a correct gene expression pattern and, as such, its misregulation has been implicated in a variety of human diseases. In the lab, we are currently investigating RNA-misprocessing in cellular models, tissues and biofluids of patients with neurodegenerative diseases in order to develop (i) personalized antisense RNA-based therapeutic strategies using RNA-targeting CRISPR-dCas13 system and (ii) sensitive RNA detection methods that could serve as future biomarkers for disease diagnosis. In Frontotemporal dementia, we have combined bioinformatic and experimental approaches to characterize the molecular mechanism of a non-coding mutation in GRN gene, which leads to an aberrant splicing pattern that causes GRN mRNA degradation and progranulin haploinsufficiency. We are currently exploiting CRISPR-dCas13 RNA targeting system in order to identify sequences in GRN pre-mRNA whose targeting using antisense RNAs would restore GRN reading-frame. Based on this concept, we would like to develop a personalized therapeutic approach for patients with this mutation. Another aim in the lab is to perform and exploit computational analysis of RNA-seq data in order to investigate RNA-misprocessing events relevant for disease etiology and to develop sensitive RNA quantification methods which can be used as future biomarkers of neurological diseases. Specifically, we are developing targeted RNA-sequencing approaches to quantify cryptic polyadenylation in disease models of TDP43-proteinopathies and Huntington’s disease. Another aim in the lab is to understand the contribution of RNA-missprocessing to glioblastoma pathogenesis, the most common primary brain tumor of the central nervous system, as well as the most lethal glioma type. For that, we use publicly available RNAseq data from the Chinese Glioma Genome Atlas (CGGA) and high-grade glioma biopsies from patients who undergo tumor resection in Donostia University Hospital, where we isolate glioma stem cells (GSCs). Our final goal is to identify new targets which can be exploited as future therapeutic and/or diagnostic markers.