The field of interest applies to the study of the molecular basis of neurodegenerative diseases and to the exploitation of novel RNA-based therapies. In particular, this project aims to discover new mechanisms of gene expression regulation controlled by non coding RNAs (ncRNAs) and how they impact in neuronal differentiation and in neurodegenerative disorders, such as Amyotrophic lateral sclerosis (ALS). This is one of the most common motor neuron disease whose pathogenic relevance is linked to altered RNA binding proteins (RBP), such as FUS and TDP-43, and defective RNA metabolism. Mutations in these proteins induce the formation of insoluble cytoplasmic aggregates, feature which is common to many neurodegenerative diseases.
Recent works indicate that also RNA and aberrant ribonucleoprotein (RNP) formation has an important pathogenic relevance in such diseases. How defective RNPs form, what are their integral components and which events trigger their appearance late in life are still unsolved issues.
This project aims to combine innovative computational approaches, imaging methodologies and powerful genetic tools to characterize RNP complexes and how they are modified in disease conditions. Moreover, we plan to develop new RNA molecules (aptamers) able to counteract aggregate formation and to impede pathological cascades driven by RNP assemblies.
This research holds promise for a significant increase in our understanding of basic molecular processes controlled by ncRNAs and should also constitute a largely unexplored territory for the development of novel therapeutics and diagnostics.
RNA systems biology is a young and rapidly growing research field, which has been largely fueled by new technologies such as NGS and advanced bio-imaging. Novel RNA function represents one of the most exciting and challenging fields of contemporary molecular biology. This is because the cellular and organismal contributions of most molecules predicted from eukaryotic genomes remain unknown. It is clear, however, that aberrant RNA levels correlate strongly with human disease phenotypes and that RNA-associated complexes themselves are tightly linked to disease biology. Thus, further development of innovative experimental methodologies coupled with state of-the-art computational biology is imperative to advance both basic and applied research.
We expect our project to generate ground-breaking discoveries on the mechanisms of RNP organization and their link with cellular function and dysfunction, including diseases caused by aberrant protein aggregates. Beyond the study of ALS, our project will provide a unique framework to understand the molecular determinants of neurodegenerative disorders. Our studies will uncover new molecules with the capacity to modulate the extent and speed of MN differentiation from Pluripotent Stem Cells. Those new molecules will be RNA molecules possibly regulating
endogenous RNA transcription, biogenesis, stability, and translation. Therefore, they can be used as a new set of targets or molecular tools for cell therapy, to instruct a more precise differentiation of
medically relevant cells (IPSCs) in the context of physiological or pathological neurodegeneration.
Finally, the applicability of aptamers as reagents to interfere with protein aggregates represents a potentially powerful novel strategy for the cure of neurodegenerative diseases which corrupt the structure and function of RNA-binding proteins. The employment of RNA molecules over nucleotide mimetics or targeted drug design will limit the contingent immunogenicity. Compared to other currently employed RNA technologies, the aptamers we are developing within this project are significantly shorter, reducing production costs and experimental variability. Moreover, our computational methods to predict protein-RNA interactions provides an innovative and original alternative to design RNA aptamers overcoming the limitations of SELEX in terms of the time, cost and without the need of physical oligonucleotide libraries.
The innovative approaches developed in the course of the project will be made available to the scientific community as a valuable resource and both knowledge and reagents generated. The integration of scientists from diverse disciplines who bring together a variety of expertise that are required for the completion of a project of this scope represents a further added value.