Dataset Information

VCP D1 ATPase activation enhances both autophagic and proteasomal neurotoxic protein clearance

ABSTRACT: Autophagy upregulation enhances the clearance of various neurotoxic proteins and ameliorates their toxicities in disease models. Thus, autophagy activators may have therapeutic utility. Here, we have identified the essential protein VCP/p97 as a target of the autophagy-inducing molecule SMER28, providing a mechanism for a molecule that has shown promising results in animal models of neurodegeneration. SMER28 stimulates VCP D1 ATPase activity to activate autophagy by enhancing interactions of PI3K complex components to increase PI(3)P production and consequent autophagosome formation. Interestingly, SMER28-mediated increase in VCP D1 ATPase activity also enhances degradation of short-lived misfolded and aggregate-prone proteins through the ubiquitin-proteasome system (UPS). We further show that another recently described activator of VCP induces autophagy and UPS flux in a comparable manner, providing additional evidence that targeting VCP D1 ATPase domain could be a useful approach for clearance of aggregate-prone proteins by both autophagy-lysosome and proteasomal routes.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Escherichia Coli

SUBMITTER: Nigel Beaton

LAB HEAD: David C. Rubinsztein

PROVIDER: PXD027750 | Pride | 2022-07-15

REPOSITORIES: Pride

ACCESS DATA

Similar Datasets

Project description:Genomic, proteomic, and metabolomic technologies continue to receive increasing interest from environmental toxicologists. This interest is due to the great potential of these technologies to identify detailed modes of action and to provide assistance in the evaluation of a contaminant?s risk to aquatic organisms. Our experimental model is the zebrafish (Danio rerio) exposed to reference endocrine disrupting compounds in order to investigate compound-induced changes in gene transcript profiles. Adult, female zebrafish were exposed to 0, 15, 40, and 100 ng/L of 17 alpha-ethynylestradiol (EE2) and concentration and time-dependent changes in hepatic gene expression were examined using Affymetrix GeneChip® Zebrafish Genome Microarrays. At 24, 48, and 168 hours, fish were sacrificed and liver mRNA was extracted for gene expression analysis (24 and 168 hours only). In an effort to link gene expression changes to effects on higher levels of biological organization, body and ovary weights were measured and blood was collected for measurement of plasma steroid hormones (17 beta-estradiol (E2), testosterone (T)) and vitellogenin (VTG) using ELISA. EE2 exposure significantly affected GSI, E2, T, VTG and gene expression. We observed 1575 genes that were significantly affected (up- or down-regulated by at least 1.5-fold (p ? 0.001) in a concentration-dependent manner by EE2 exposure at either 24 or 168 hours. EE2 exposure altered transcription of genes involved in steroid hormone homeostasis, cholesterol homeostasis, retinoic acid metabolism, and cell growth and proliferation. Plasma VTG was significantly increased at 24, 48, and 168 hours (p<0.05) at 40 and 100 ng/L and at 15 ng/L at 168 hours. E2 and T were significantly reduced following EE2 exposure at 48 and 168 hours. GSI was decreased in a dose-dependent manner at 168 hours. In this study, we identified genes involved in a variety of biological functions that have the potential to be used as markers of exposure to estrogenic substances. Future work will evaluate the use of these genes in zebrafish exposed to weak estrogens to determine if these genes are indicative of exposure to estrogens with varying potencies.

Dataset Information

VCP D1 ATPase activation enhances both autophagic and proteasomal neurotoxic protein clearance

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure