Final Report Summary - RIBOMYLOME (The Role of Non-coding RNA in Protein Networks and Neurodegenerative Diseases)
We combined computational and experimental work to unravel properties of non-coding RNAs. In the context of neurobiology, we investigated which interactions proteins establish with non-coding RNAs and the implications for cellular function and dysfunction. We aimed to discover the involvement of transcripts in regulatory networks controlling protein production. More specifically, we were interested in understanding mechanisms whose alteration lead to aberrant accumulation of proteins.
We built a novel theoretical method to predict protein-RNA interactions that were validated experimentally using state-of-the-art techniques. With our approach, we discovered a number of RNA-binding proteins, such as TRA2A, that coalesce in large assemblies or granules. Our results indicate that uncontrolled interactions of protein and RNA material is toxic, which opens up the avenue for further investigations in the area of neurodegeneration. One main finding is that mutations trap proteins such as TDP43 in a semi-soluble, liquid-like state that damages the cell by favouring aberrant interactions.
We also studied the role of protein-RNA interactions in the context of Parkinson’s disease. In agreement with our computational predictions, we found protein-RNA mechanisms inducing changes in alpha-synuclein levels that are compatible with those observed in idiopathic Parkinsonism and proposed a novel biomarkers. We investigated the role of RNA structure in promoting protein interactions and we built a novel approach that predicts single and double-stranded regions within transcripts. We discovered that specific RNAs bind to proteins in large, granule-like assemblies that are implicated in a number of disorders, including as for instance Fragile X Tremor Ataxia/Syndrome (FXTAS).
Most importantly, we used our approaches to unravel interaction networks of a large number of non-coding RNAs with novel experimental approaches, introducing methods and concepts that can be exploited for future studies (and not only in the context of neurodegeneration).
We built a novel theoretical method to predict protein-RNA interactions that were validated experimentally using state-of-the-art techniques. With our approach, we discovered a number of RNA-binding proteins, such as TRA2A, that coalesce in large assemblies or granules. Our results indicate that uncontrolled interactions of protein and RNA material is toxic, which opens up the avenue for further investigations in the area of neurodegeneration. One main finding is that mutations trap proteins such as TDP43 in a semi-soluble, liquid-like state that damages the cell by favouring aberrant interactions.
We also studied the role of protein-RNA interactions in the context of Parkinson’s disease. In agreement with our computational predictions, we found protein-RNA mechanisms inducing changes in alpha-synuclein levels that are compatible with those observed in idiopathic Parkinsonism and proposed a novel biomarkers. We investigated the role of RNA structure in promoting protein interactions and we built a novel approach that predicts single and double-stranded regions within transcripts. We discovered that specific RNAs bind to proteins in large, granule-like assemblies that are implicated in a number of disorders, including as for instance Fragile X Tremor Ataxia/Syndrome (FXTAS).
Most importantly, we used our approaches to unravel interaction networks of a large number of non-coding RNAs with novel experimental approaches, introducing methods and concepts that can be exploited for future studies (and not only in the context of neurodegeneration).