Systematic and mechanistic assessment of the roles of circRNAs in Alzheimer's Disease

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PROJECT SUMMARY Control of RNA metabolism is emerging as a major hub for regulation in the brain. Therefore, it is not surprising that there is a strong link between perturbation of RNA metabolism and a number of neurological and neurodegenerative diseases. These include Alzheimer’s Disease (AD) in which Tau protein and Aß42 fragments have been shown to interact and/or modulate directly or indirectly RNA binding proteins and RNA metabolism in general. Circular RNAs (circRNAs) are highly abundant RNAs produced by circularization of specific exons. Interestingly, circRNAs accumulate in an age-dependent manner in neural tissues suggesting their relevance to age-related homeostasis and/or pathogenesis. Indeed, specific circRNAs accumulate in the brains of individuals with Parkinson’s and Alzheimer’s diseases. However, how these circRNAs are involved in the pathogenesis of those and other neurodegenerative diseases is largely unknown. We recently developed systems to down- or up-regulate circRNAs in Drosophila. Using these tools, we demonstrated the functionality of these molecules in vivo. We generated a resource to knock down (KD) the 110 more abundant circRNAs and found that KD of particular circRNAs results in different brain-related phenotypes. Interestingly, we identified 35 circRNAs that when knocked down alter lifespan. Further data shows that expression of some circRNAs is toxic for the aging fly, with links to aging and potentially neurodegeneration. In addition, we found that KD of some circRNAs lead to specific behavioral and motor defects, many of which are age-dependent. In addition, we observed changes in the levels of circRNAs in Drosophila models of AD or other neurogenerative diseases. Here we aim to uncover the functions and mechanisms of action of circRNAs during AD. To do so, we will use Drosophila AD models and perform a genomic screening to determine if modulation of individual circRNAs can alter the progression and outcome of the disease. Moreover, we will also test potential mechanisms by which circRNAs could alter AD including nucleation of aggregates, altering mitochondrial function, autophagy, apoptosis, and/or inflammation. In sum, the present proposal will reveal new roles of circRNAs during AD. As we will perform the experiments in a system that has high and functional levels of circRNAs (the fly CNS) the present results will be meaningful and could be later extended to mammalian models. We are aware of the limitations of the AD fly models but this is the only system in which the full extent of interaction with a large number of circRNAs can be assessed. Moreover, as we have already found that some circRNAs alter aging, the chances of success are high. This will be a pioneering work in this new and important area of research and we are confident that our findings will open a new pathway for studying the roles of circRNAs in AD. Our project builds on exciting preliminary results and the unique and constantly evolving expertise of our group.