Pathogenic role of paraspeckle-like nuclear bodies in neurodegenerative diseases ALS and FTD

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two phenotypic manifestations of a devastating neurodegenerative disease spectrum. Cytoplasmic mislocalization and aggregation of otherwise nuclear RNA binding proteins are the hallmark pathological features of both. In 95% of all ALS and 60% of FTD patients the aggregating protein is TDP-43, thus defining those cases as TDP-43 proteinopathies. However, only a very small percentage of aggregation is actually caused by mutations within TDP-43. To understand the disease processes and find novel treatment approaches, discerning signaling pathways causative for aggregation of wildtype TDP-43 became the main focus of the ALS and FTD research fields. Changes in TDP-43 localization were shown to arise also from disease-causing mutations in other genes, the most common being TDP-43 proteinopathy-associated GGGGCC hexanucleotide repeat expansion (HRE) mutation in C9ORF72 gene.

The aim of this project is the characterization of structure and function of hexanucleotide repeats RNA foci in the context of their role in pathogenesis of ALS and FTD, converging on regulation of their formation as an approach to therapy.

We will achieve our goals by implementing the newest cutting-edge procedures, such as RBPomics, transcript specific RBDmapping, and advanced bioinformatics that are all available to collaborating groups. These will, in combination with validation in newly established disease models and patient tissues, provide a profound insight into crucial neurodegeneration-related molecular processes and facilitate the search for cures. By unraveling structural and functional characteristics of HRE RNA foci, the proposed project will lead into a new research direction development, displaying essential for understanding regulation and pathogenesis of C9ORF72-associated diseases, as well as understanding the basic role of RNP in the nucleus.