Role of circular RNAs in autophagy regulation and neuronal development and function in psychiatric disorders

点击翻译按钮获取中文摘要

Although ignored until recently for not complying with the central dogma of molecular biology, non-coding RNAs (ncRNAs) are emerging as important novel regulators of diverge cellular processes. The capacity of ncRNAs to engage in "molecular multitasking" positions them to link multiple genetic risk factors for polygenic human genetic disorders, such as psychiatric diseases, into functional networks. Circular RNAs (circ RNAs) are a novel category of non-coding RNAs that are derived from the back-splicing and covalent joining of exons and introns of protein-coding genes, yet lack the capacity to become translated into protein. Recent studies have suggested that circ RNAs are enriched in the brain, are developmentally regulated, and are abundant in dendrites and synapses. Despite this, nothing is known about the function of circ RNAs in the mammalian brain and their potential involvement in autophagy and neuro psychiatric disease. Autophagy is a coordinated lysosomal process for the degradation and recycling of cellular components, organelles, and protein aggregates that has been heavily implicated in the pathophysiology of neurodegenerative disorders. However, recent data suggest that numerous autophagy-associated genes display reduced expression in postmortem brains of subjects with psychiatric disorders and that neurons utilize autophagy during normal neuronal development and function. Despite the above, the importance of autophagy in psychiatric disease pathogenesis and pathophysiology has not been fully elucidated. Our proposed research aims in examining the role of altered in psychiatric disorders circ RNAs that are either derived from autophagy-related genes or are upstream regulators of autophagy gene expression in neuronal autophagy and development and function. I specifically propose the following 3 aims. Aim 1: Test the hypothesis that alterations in psychiatric disease-associated circRNAs dysregulate linear gene expression related to autophagy and neuronal development and function. Aim 2: Test the hypothesis that manipulation of psychiatric disease-related circ RNAs ca n alter autophagy and neuronal development and function. Aim 3: Test the hypothesis that treatment with autophagy- inducing drugs ca n rescue circ R NA- mediated alterations in neuronal development and function. Take n together our proposed research will elucidate the mechanisms that underlie the effects of autophagy-associated circ RNAs on neuron a l autophagy and function, while examining in parallel the irrelevance for psychiatric disease therapeutics.