RP1: Identification of ubiquitin-dependent pathways involved in neuron-specific protein degradation

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The ubiquitin/proteasome system (UPS) is pivotal for the elimination of misfolded or regulatory proteins, and plays a crucial role in correct neuronal development and function. Attachment of several ubiquitin molecules in form of a polyubiquitin chain usually involves three classes of enzymes: a ubiquitin-activating enzyme (El), a ubiquitinconjugating enzyme (E2), and a ubiquitin ligase (E3). In some cases however polyubiquitylation requires the additional activity of ubiquitin chain elongation factors, termed E4 enzymes.The central objective of our proposed research is to identify ubiquitin-dependent pathways involved in neuron-specific protein degradation. Using green fluorescent protein (GFP)-based substrates that allow rapid quantification of ubiquitin-dependent proteolysis, we have established an in vivo degradation assay in different tissues of the model organism Caenorhabditis elegans. The identification of proteolytic pathways specific for neurons and other tissues will provide novel mechanistic insights into the UPS and neuronal differentiation.