The role of the E3 ligase RNF157 in neuronal survival

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Neuronal cell death is a hallmark of neurodegenerative diseases. However, our understanding of the underlying mechanisms is very limited. The ubiquitin proteasome system has emerged as a crucial regulator of various neurodevelopmental events including neurogenesis, migration, axon and dendrite growth, and synapse formation. However, little is known about the role of the UPS in neurodegeneration. Among the components that comprise the UPS, E3 ubiquitin ligases are the most numerous. Mahogunin-1 is one of the few E3 ligases, which have been implicated in neurodegeneration. The goal of the proposal is to delineate the mechanism underlying the Mahogunin-1-related E3 ligase RNF157 in neuronal survival. Our preliminary data indicate a prosurvival role of the brain-specific protein RNF157 in neurons. Also, we identified the scaffold protein FE65 as an interactor of RNF157 and found that FE65 gain-of-function induces apoptosis. In addition, we have established an RNF157 knockout mouse, that is embryonic lethal. The aims of the proposed research are as follows: The first aim will be the histological and behavioral analyses of RNF157 knockout mice. Here, we will analyze both homozygous and heterozygous mice at the histological level and examine heterozygous RNF157 animals with behavioral tests. With the second aim, we will delineate the RNF157 pathway of neuronal survival. The proposed experiments will examine the RNF157-FE65 interaction in neuronal survival using loss- and gain-of function analyses together with structure-function analyses. Taken together, this proposal will examine the novel E3 ligase RNF157 in neuronal survival to shed light onto novel pathways that support neuronal health and ultimately allow a better understanding of neurodegenerative processes.