Axon guidance receptors regulate neuron survival through mitochondria regulation

The nervous system is a complex network of neurons that requires the specific connectivity of axons and dendrites to function properly. For proper connection to occur, neuronal processes must grow out from the cell body and be guided toward the proper target and then select the proper target to form a synapse. Because of the vast number of neurons making up the nervous system, the cues that guide processes to a specific target must have a great degree of molecular variability in order to distinguish one cell from another. One molecular cue that helps pattern the nervous system is the Down syndrome cell adhesion molecule, or Dscam. Dscam endows neurons with a molecular self-recognition mechanism that repels sister neurite branches away from one another, allowing for the innervations of multiple discrete targets by the same neuron. We are now investigating a new role for Dscam in an apoptosis pathway. We are especially excited about this result because of the implications of Dscam functioning in neurodegeneration pathways. We have developed a genetic system to screen for genes that modify Dscam gain-of-function phenotypes. This has resulted in a fantastic tool for the identification of genes that control either Dscam mediated repulsion or Netrin mediated attraction and perhaps neuron survival. In this system, ectopic expression of a particular Dscam isoform results in two distinct phenotypes: exuberant dispersion of sister neurite branches (exhibiting repulsion) and dorsal ectopic targeting (exhibiting attraction) of a subset of fibers. We are now examining a new role for the Dscam-Netrin interaction in programmed cell death. Interestingly, we have found that the two Drosophila Netrins function oppositely in apoptosis, with NetrinA being pro-apoptotic and NetrinB being anti-apoptotic. We are now exploring behavioral deficits that indicate a loss of coordination as a fly ages when lacking certain proteins of this pathway. We are currently focusing on understanding the interactions involving Dscam, Frazzled (a Netrin receptor), and the Netrins. We hope to more fully define the pathways in which these molecules are affecting apoptosis, and in doing so begin to understand how Dscam, Frazzled, and Netrin interact to prevent neurodegenerative disease. Our most recent findings suggest that the Netrins interact with Parkin, a protein that is mutated in some forms of Parkinson\u27s disease. We find that loss of NetrinB is able to rescue Parkin mutant phenotypes, while loss of NetrinA enhances them. However, interestingly, loss of NetrinB combined with loss of Parkin substantially increases fly susceptibility to Paraquat, a drug that increases production of reactive oxygen species. We are now in the process of determining how the Netrins function in mitochondrial activity and how they interact with Parkin, so as to better understand how Dscam, Netrins, and Parkin are functioning in neurodegeneration