Genetic studies in model organisms have provided tremendous insights into neural development and revealed surprising similarities between vertebrates and invertebrates in the genes and pathways controlling the patterning and wiring of the nervous system. Compared to neural development, much less is known about the molecular and cellular mechanisms that help maintain the integrity and function of the diverse differentiated neurons after they are fully developed and integrated into neural circuits. It is expected that elucidation of the mechanisms central to neuronal maintenance in model organisms will inform similar processes in humans, impairments of which underlie various neurodegenerative conditions such as Alzheimers disease and Parkinsons diseases, for which there is currently no effective treatment. Drosophila has served as an excellent model system to elucidate the signaling network that directs mitochondrial quality control, a multifaceted process encompassing fission/fusion dynamics, transport, and autophagy (mitophagy). This mitochondrial quality control process is crucially important for the structural and functional integrity of dopaminergic neurons, the cell types that are lost to Parkinsons disease. Our recent genetic studies have revealed novel roles of the conserved target of rapamycin signaling complexes (TORC1 and TORC2) in regulating mitochondrial function and maintaining dopaminergic neuron integrity, although paradoxically TORC1 and TORC2 exhibit opposite effects in this process. The goal of this proposal is to use molecular genetic, genomic, biochemical, and cell biological tools available in Drosophila to decipher the mechanisms of action of TORC1 and TORC2 in mitochondrial regulation, in an effort to understand in molecular terms how mitochondrial abnormality arises and how it impacts neuronal integrity in age-related neurodegenerative disease conditions. The hypothesis to be tested is that TORC1 and TORC2 play central roles in dopaminergic neuron maintenance by directing distinct aspects of mitochondrial regulation, with TORC2 regulating mitochondrial quality control whereas TORC1 regulating mitochondrial respiratory chain complex biogenesis through translational regulation. Key findings from the fly studies will be validated in patient-derived, dopaminergic neuron-based disease models. Greater understanding of the functions of the genes to be studied in this project will provide novel insights into the fundamental mechanisms linking mitochondrial regulation to neuronal maintenance. This will ultimately contribute to the treatment of a host of neurodegenerative conditions associated with mitochondrial dysfunction.

Public Health Relevance

This proposal aims to employ the powerful tools available in the model organism Drosophila to elucidate fundamental mechanisms by which conserved cellular signaling pathways influence the function of mitochondria, the cellular organelles that make ATP. This process is central to the maintenance of dopaminergic neurons that are lost to Parkinson's disease. Key findings from the Drosophila studies will be validated using novel disease models built with Parkinson's disease patient-derived induced dopaminergic neurons. Knowledge to be gained from this study will help understand and ultimately treat Parkinsons disease and a host of disease conditions caused by mitochondrial dysfunction.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-ETTN-G (03))
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Sutherland, Margaret L
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Stanford University
Schools of Medicine
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Lee, Kyu-Sun; Huh, Sungun; Lee, Seongsoo et al. (2018) Altered ER-mitochondria contact impacts mitochondria calcium homeostasis and contributes to neurodegeneration in vivo in disease models. Proc Natl Acad Sci U S A 115:E8844-E8853
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