Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable and fatal neurodegenerative diseases with complex etiologies. One pathogenic factor is a mutation in the C9orf72 gene, in which the six-nucleotide sequence GGGGCC/GGCCCC (HR) is abnormally expanded. The effect of such a mutation on cell function is observed, among others, at the RNA level. Transcripts containing expanded HR sequences exhibit structural polymorphisms and can adopt various secondary and tertiary structures. These structures are responsible for the downregulation of proteins that are essential for cell function and serve as template for the production of toxic polypeptides. Currently, many ongoing studies are focused on the development of effective ALS/FTD therapies. One approach is to develop small ligands that bind to RNA and block its pathogenic activity. However, this process is hampered by the lack of three-dimensional structures of pathogenic RNAs and their complexes with small ligands. This could provide knowledge on how to modify the ligand to increase its specificity and affinity for target RNA.

A team of scientists from the ICHB PAS, led by Dr. Agnieszka Kiliszek (Dr. Leszek Błaszczyk, Dr. Marcin Ryczek, M.Sc. Martyna Mateja-Pluta, Dr. Magdalena Bejger and Dr. Joanna Śliwiak), in collaboration with the group of Prof. Kazuhiko Nakatani from Osaka University (Japan), determined the three-dimensional structure of the RNA containing the GGCCCC sequence and the structure of complex of this RNA with small ligand (ANP77). These results showed that in addition to the hairpin structure, cytosine-rich RNA molecules have the potential to fold into a triplex. In addition, detailed interactions between the ANP77 ligand and RNA were determined. These studies expand our knowledge of structural polymorphisms of HR and can be used for the rational design of small molecules targeting disease-related RNAs. Publication link: https://doi.org/10.1093/nar/gkae376