Wednesday, January 15, 2025
1/15/2025
DESCRIPTION (provided by investigator): A common theme that is emerging from studies of neurodegenerative disorders is the realization that many of them are associated, or caused, by defects in protein degradation pathways involving either the ubiquitin-proteasome system or autophagy. The ubiquitin-proteasome degradation pathway is the major pathway used in cells in which misfolded, damaged, and unwanted proteins are first tagged with a chain of four or more ubiquitin molecules and is then recognized and degraded by the proteasome. The autophagy pathway is similar in many respects to the ubiquitin-proteasome degradation pathway, except that proteins as well as organelles are targeted to the lysosome instead of the proteasome. At present it is not known how cells select one or both of these pathways to degrade a particular protein. Our laboratory identified ubiquilin, the founding member of a new class of proteins that appears to regulate protein degradation in cells. During the last funding period, we discovered that ubiquilin interacts with a novel endoplasmic reticulum (ER)- and nuclear envelope-localized protein that we named erasin. We found that erasin promotes endoplasmic reticulum- associated protein degradation (ERAD), a regulated pathway in which misfolded proteins in the ER are extracted and degraded in a ubiquitin-dependent manner by the proteasome. We found that erasin levels are increased by ER stress and that both ubiquilin and erasin protein levels are increased in neurons undergoing neurofibrillary degeneration in Alzheimer's disease. In other studies we found that ubiquilin and erasin interact functionally in ERAD and that they colocalize and are required for autophagosome formation during autophagy. The goal of this proposal is to characterize the functional role of ubiquilin and erasin proteins in cells, with particular emphasis of their roles in ERAD and autophagy. We propose three aims. In Aim 1, we will determine the role of ubiquilin-erasin interaction in ERAD. In Aim 2, we will determine the role of ubiquilin-erasin interaction in autophagy. Finally in Aim 3 we will characterize erasin-interacting proteins and determine the structure and mechanism of targeting of the ER-membrane-localization sequence of erasin. Together these studies should lead to a better understanding of the function of ubiquilin and erasin in protein degradation pathways and the role of the proteins in health and pathological processes. Proteins carry out many vital functions in organisms, but to do so, they need to be correctly folded. Unfortunately proteins tend to misfold, either because they contain genetic mutations or because of environmental influences. In fact, accumulation of misfolded proteins is now known to cause many human diseases, particularly neurodegenerative diseases like Alzheimer's disease, Huntingtons's disease, Lou Gehrig's disease, and Parkinson's disease. This proposal is directed towards studies of ubiquilin and erasin, two new proteins that we discovered that are involved in the removal of misfolded proteins in cells. The results obtained from this proposal will not only lead to a better understanding of how misfolded proteins are cleared from cells, but also could lead to new therapies to treat human diseases caused by protein misfolding.
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