Defining the role of C. elegans Parkin/PDR-1 in glial engulfment of neuron fragments

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PROJECT SUMMARY Glia engulf fragments of live neurons in order to regulate specialized neuron endings. Amounting evidence indicates the engulfment of neuron fragments by glia is a broad regulatory and developmental function of glia in both the central and peripheral nervous systems. How this process is regulated under normal conditions is unclear in any system, but it was recently shown that mis-regulation of this process contributes to early synapse loss in mouse models of Alzheimer’s disease. Furthermore, mis-regulation of phagocytosis by Retinal Pigment Epithelium cell in the eye may cause some forms of macular degeneration. Synapse loss and sensory disfunction are early hallmarks of Parkinson’s disease, however the involvement of glia is unknown. Loss of function of the E3 ubiquitin ligase Parkin contributes to the onset and progression of Parkinson’s disease. The role of Parkin mediating mitophagy in neurons is well characterized in mammals and invertebrate models, but despite being expressed in several glial subtypes, the functions of Parkin in glia are unknown. We have recently shown in C. elegans that fragments of a specialized sensory neuron are engulfed by an associated glial cell. Preliminarily, I have found that loss of function of the Parkin ortholog pdr-1 elicits a substantial increase in the number neuron fragments engulfed by glia, demonstrating that PDR-1 inhibits engulfment by glia. C. elegans has historically been a powerful model used to unearth the mechanisms of phagocytosis by which cells recognize, engulf, and degrade cellular debris. I propose to use this system to probe the mechanism by which Parkin/PDR-1 regulates glial phagocytosis of neuron fragments. I will determine the cell-specific requirements of PDR-1, probe substrates of its E3 ligase activity that may have roles in glial engulfment, and finally ask if its role in mitophagy has a function in glial engulfment.