Circular RNAs (circRNAs) are an emerging class of RNA molecules with potential for prolonged expression due to their inaccessibility to exonucleases. Recent studies dissecting circRNA biogenesis have found inverted repeat sequences such as ALU repeats in humans, flanking a large number of exons that are subject to circularization and have shown these cis-elements as well as splicing machinery are essential for their circularization. In the mammalian brain, circRNAs appear to be highly abundant and dynamically regulated by development and plasticity. In particular, they appear to be enriched at the synapses and during neuronal differentiation and development. Despite these exciting advances, no systems for studying biogenesis of synthetic circRNAs in the brain and models of neurological disease.
Specific aims for the current proposal are focused on engineering circRNA expression systems, studying factors affecting circRNA biogenesis efficiency in the brain, and utilizing these systems to interrogate deregulation of splicing and RNA-induced neurotoxicity seen in a C9orf72 Hexanucleotide Repeat Expansion mouse model of Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). CircRNAs capable of disrupting the neurotoxic RNA foci seen in these mouse models may enable design of therapeutics for FTD/ALS, where the C9orf72 expansion is prevalent and believed to be causative. Overall, the current proposal will help develop new strategies for efficient biogenesis of circRNAs in animal models, which are likely to help understand factors affecting circRNA biogenesis in the mammalian brain as well as usher in a new class of nucleic acid therapeutics based on circular RNAs.
Circular RNAs (circRNAs) are an emerging class of RNA molecules with potential for tissue-specific, gene regulation and expression. Understanding and manipulating the expression profiles of these novel RNA constructs in normal and diseased mammalian brains could provide a path towards designing therapeutics with improved safety and efficacy for diseases such as Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
| Mestre, Humberto; Hablitz, Lauren M; Xavier, Anna Lr et al. (2018) Aquaporin-4-dependent glymphatic solute transport in the rodent brain. Elife 7: |
| Meganck, Rita M; Borchardt, Erin K; Castellanos Rivera, Ruth M et al. (2018) Tissue-Dependent Expression and Translation of Circular RNAs with Recombinant AAV Vectors In Vivo. Mol Ther Nucleic Acids 13:89-98 |
| Wilusz, Jeremy E (2018) A 360° view of circular RNAs: From biogenesis to functions. Wiley Interdiscip Rev RNA 9:e1478 |
| Liang, Dongming; Tatomer, Deirdre C; Luo, Zheng et al. (2017) The Output of Protein-Coding Genes Shifts to Circular RNAs When the Pre-mRNA Processing Machinery Is Limiting. Mol Cell 68:940-954.e3 |
