Molecular Genetic Analysis of TORC1 and TORC2 Signaling in Neuronal Maintenance

Stanford University, Stanford CA

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Abstract

DESCRIPTION (provided by applicant): 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.