RP10: Role of Parkin in regulating GDNF signal transduction and receptor turnover in neurons

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Mutations in the ubiquitin protein ligase parkin can cause Parkinson s disease (PD) by altering protein turnover. Parkin polyublquitylates some substrates to mark them for degradation by the proteasome and others, such as Eps15, are monoubiquitylated. Monoubiquitylated Eps15 can not bind to cell surface receptors and trigger clathrindependent endocyotsis, thereby enhancing receptor signaling.Work from my laboratory suggests that parkin and Eps15 also regulate the protein turnover of the glial cell line-derived neurotrophic factor (GDNF) receptor Ret in neurons. We found that Ret can bind to Eps15 and parkin; parkin alters the internalization of GDNF; and the amount of Ret protein seems to be reduced in parkin-deficient mice.In this project, we will investigate how parkin, Eps15 and Ret interact; how this interaction is regulated; and how parkin influences the internalization, degradation and signaling of Ret in neurons by performing biochemical and cell culture experiments. In addition, we will study the physiological relevance of this interaction in double transgenic parkin and Ret mice and by analyzing brain tissue from PD patients with mutations in parkin. These data will allow Integrating Ret in the protein network altered in PD patients and will enhance our understanding of this complex disease.