Project Summary: An intersection between neural development and neurodegeneration processes is increasingly being recognized in many neurological diseases, including neurodevelopmental and psychiatric diseases such as schizophrenia. Understanding the molecular basis underlying the connection between these two seemingly disparate processes promises to provide fundamental insights into the logic and principles of neuronal development and maintenance. Mitochondria are dynamic and complex organelles with essential roles in many aspects of biology, from energy production and intermediary metabolism to apoptosis and Ca2+ buffering. Mitochondrial dysfunction has been observed early on in neurodegenerative diseases such as Parkinson?s disease and in diseases suspected to have both neurodevelopmental and neurodegenerative components such as schizophrenia. How mitochondrial dysfunction arises in the disease process, and the exact roles of mitochondria in neuronal development and maintenance are not well understood. In this project we propose to test the hypothesis that the tRNA Splicing Endonuclease (TSEN) complex acts through regulation of mitochondrial function to influence neuronal development and maintenance. Genetic mutations in TSEN have been linked to Pontocerebellar Hypoplasia (PCH), a rare congenital disorder characterized by neurodevelopmental deficits as well as neurodegeneration. The molecular function of TSEN and the cellular mechanism of TSEN dysfunction on neuronal development or maintenance are poorly understood. Based on compelling preliminary results, we hypothesize that the TSEN complex critically regulates the metabolism and/or translation of nuclear encoded respiratory chain component (nRCC) mRNAs to maintain mitochondrial function. To test this hypothesis, we propose to achieve two Specific Aims. In Aim 1, we seek to firmly establish the mitochondrial basis of TSEN-associated disease pathogenesis. In Aim 2, we intend to determine the molecular mechanisms by which the TSEN complex regulates mitochondrial function. Drosophila TSEN models will be extensively used in this project. Our lab is highly experienced in the use of Drosophila as a model to dissect cellular signaling pathways commonly involved in regulating nervous system development and maintenance, in an effort to gain novel insights into the pathogenesis of neural developmental and degenerative diseases. We are particularly experienced in studying the role of mitochondria in these fundamental processes. Using the techniques we have developed and the expertise we have acquired, we aim to generate the first in vivo evidence that TSEN critically regulates mitochondrial function. We anticipate that results from this study will set the stage for future mechanistic studies of TSEN regulation of mitochondria using Drosophila as a model, which promises to inform the understanding and treatment of other neural developmental/degenerative disorders with similar mitochondrial etiologies.