Elucidating the neural specific functions of the RNA-binding protein Caper in neural development and neurodegeneration

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Project Summary/Abstract Post-transcriptional gene regulation is a fundamental mechanism that helps regulate the development and healthy aging of the nervous system. Mutations that disrupt the function of RNA-binding proteins (RBPs), which regulate post-transcriptional gene regulation, have increasingly been implicated in neurological disorders including amyotrophic lateral sclerosis, Fragile X Syndrome, and spinal muscular atrophy. Interestingly, although the majority of RBPs are expressed widely within diverse tissue types, the nervous system is often particularly sensitive to their dysfunction. The long-term goal of this project is to begin to elucidate how aberrant RNA regulation that results from the dysfunction of ubiquitously expressed RBPs, leads to tissue specific pathologies that underlie neurological diseases. To this end, the highly conserved splicing factor Caper will be used as a model. Caper is widely expressed throughout development and is required for the development of Drosophila sensory and motor neurons. Furthermore, caper dysfunction causes neurodegeneration and results in adult locomotor deficits. Though little is known about the function of the human caper ortholog, RBM39, it is expressed within the nervous system suggesting its neural functions may be conserved. The research proposed within this application will test the hypothesis that Caper regulates RNA targets in a combinatorial manner within neuronal cells by participating in specific ribonucleoprotein complexes (RNPs) within the nervous system. We have identified proteins encoding RBPs that interact with Caper only within the brain, along with neural specific Caper target RNAs. Using the highly tractable model, Drosophila, tissue specific molecular genetic manipulations will be used in conjunction with biochemistry to determine the extent to which Caper functions combinatorially with these RBPs to direct neurogenesis and protect the aging brain from neurodegeneration. Furthermore, we will further characterize the neurodegenerative phenotypes associated with caper dysfunction to determine which cell types are undergoing cell death in the aging brain. Since aberrant RNA regulation has emerged as a common theme in various neurodegenerative and neurodevelopmental disorders, the knowledge gained from this study has broad implications for understanding and treating neurological disorders.