Characterizing new genes that govern mitochondrial function in the axon

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Abstract Mitochondria are integral to neuronal health. Subsequently, deficits in mitochondrial function contribute to a wealth of neurodegenerative diseases, where axonal dysfunction and die back usually precedes cell body demise. However, we know relatively little about the basic biology of mitochondrial biogenesis, morphological changes, transport, or function in axons in vivo. The discovery and characterization of new molecules regulating fundamental aspects of mitochondrial biology in axons may `open the door' to entirely new lines of research in neurodegenerative disease. In this proposal we aim to discover new regulators of mitochondria function in the axon using a novel and high throughput unbiased forward genetic screening approach recently developed in the lab. This approach allows us to assay mitochondrial morphology, number, and distribution in axons with unprecedented single axon and single mitochondrion resolution in vivo. Newly identified mitochondrial genes will then be characterized using an array of new tools we have optimized for mitochondrial studies in Drosophila, and we will determine precisely how mitochondrial physiology has been altered in vivo. We will also genetically determine how novel mitochondrial regulating genes function in defined pathways to control mitochondrial maintenance. Given that mitochondrial health and function is tightly correlated with neurodegenerative disease, it is likely that a number of these genes will play causal and/or accessory roles in neurodegeneration. We will therefore also investigate whether these novel mitochondria associated molecules have an exacerbated phenotype in dopamine neurons, since they selectively degenerate in Parkinson's disease (PD), a condition where mitochondrial dysfunction and oxidative stress is thought to play a fundamental role in disease progression. Functional conservation of these new molecules will then be assayed in mammalian neurons in vitro. This effort represents (to the best of our knowledge) the first high through forward genetic screen for molecules required for mitochondrial transport to and maintenance in axons. Thus a wealth of novel regulators of neuronal mitochondria, which have potential roles in neurological disease, await identification.