1:Biodonostia Institute; 2:Donostia University Hospital; 3:Ikerbasque, Basque Fundation for Science

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two types of progressive and fatal neurodegenerative diseases. Also known as TDP-43 proteinopathies, they are characterized by nuclear depletion and cytoplasmic deposition of TDP-43, a RNA binding protein with a central role in RNA metabolism and processing. Therefore, multiple altered splicing events are expected upon TDP-43 nuclear depletion. In the present project, we have analysed transcriptome alterations in the context of FTD and ALS in order to identify RNA-misprocessing events relevant for disease etiology and diagnosis. First, we performed computational analysis of RNA-seq data in peripheral blood and cellular models from FTD patients and control subjects, which exposed a sort of splicing events and possible predictive signatures of disease development. Moreover, we have confirmed that cryptic polyadenylation of STMN2 is a sensitive biomarker for TDP-43 proteinopathies with tissue specificity. Based on these results, we are currently developing a sensitive RNA quantification method, based on a targeted RNA-sequencing approach, in order to quantify in a high-throughput manner RNA misprocessing events which can be applied for disease diagnosis and monitorization.