·What is the problem/issue being addressed?
The aim of the project stands on the evidence that altered RNA metabolism and aberrant ribonucleoprotein (RNP) assembly are causatively linked to several neurodegenerative diseases, such as Amyotrophic lateral sclerosis. The experimental plan is aimed at unraveling the composition and dynamics of RNP assemblies in normal and pathological conditions, to understand the role of non coding RNAs (ncRNAs) in the control of their structure and function and finally to reveal the molecular determinants of liquid phase separation and liquid-to-solid phase transition.
The knowledge about the composition of pathological aggregates in ALS should enable the setting up of methodologies and approaches that could be applied to other neurodegenerative diseases characterized by the pathological aggregates.
The objectives revolve around the main idea that once the determinants of aggregation are identified, intervention by using a molecular approach, such as RNA aptamers, can be exploited for therapeutic intervention.
·Why is it important for society?
Many neurodegenerative disorders are still lacking effective therapeutic treatments and drugs that can counteract the progression of the disease. Even if these diseases are characterized by different genetic alterations, they share the common feature of being causatively linked to the formation of pathological aggregates. These aggregates can exert their pathological role by sequestering factors important for the activity of neuronal cells and preventing their correct function. Therefore, the deep characterization of the RNA and protein aggregates in different neurodegenerative disorders has a strong impact on human health. Our effort is mainly aimed to study the formation of aggregates in ALS; the knowledge of how they are made and how they are regulated will offer a unique opportunity for the identification of reagents able to interfere with their formation or even to direct their disassembly. Beyond the scientific relevance of this problem, there is the important question we intend to answer of which disease-related genomic alterations predispose individuals to contract neurodegenerative diseases such as ALS.
-What are the overall objectives?
We plan to develop novel advanced microscopy methods to monitor formation of aberrant RNPs in vivo as a novel early diagnostic predictive tool; moreover, we will explore new molecules to impede pathological cascades driven by aberrant RNP assemblies. In conclusion, ASTRA will allow us to gain a comprehensive understanding of RNP function and dysfunction; we will use this knowledge to develop novel therapeutic strategies that will impact on several protein-misfolding neurodegenerative diseases.
