AI Article Synopsis
Article Abstract
In mammalian cells, cytoplasmic protein aggregates generally coalesce to form aggresomal particles. Recent studies indicate that prion-infected cells produce prion protein (PrP) aggresomes, and that such aggregates may be present in the brain of infected mice. The molecular activity of PrP aggresomes has not been fully investigated. We report that PrP aggresomes initiate a cell stress response by activating the RNA-dependent protein kinase (PKR). Activated PKR phosphorylates the translation initiation factor eIF2alpha, resulting in protein synthesis shut-off. However, other components of the stress response, including the assembly of poly(A)+ RNA-containing stress granules and the synthesis of heat shock protein 70, are repressed. In situ hybridization experiments and affinity chromatography on oligo(dT)-cellulose showed that PrP aggresomes bind poly(A)+ RNA, and are therefore poly(A)+ ribonucleoprotein complexes. These findings support a model in which PrP aggresomes send neuronal cells into untimely demise by modifying the cell stress response, and by inducing the aggregation of poly(A)+ RNA.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bbamcr.2007.10.008 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
The E3 Ubiquitin Ligase TRAF6 Interacts with the Cellular Prion Protein and Modulates Its Solubility and Recruitment to Cytoplasmic p62/SQSTM1-Positive Aggresome-Like Structures.
Mol Neurobiol
March 2022
Department of Neuroscience, Scuola Internazionale Superiore Di Studi Avanzati (SISSA), Via Bonomea 265, 34136, Trieste, Italy.
The cellular prion protein (PrP) is a ubiquitous glycoprotein highly expressed in the brain where it is involved in neurite outgrowth, copper homeostasis, NMDA receptor regulation, cell adhesion, and cell signaling. Conformational conversion of PrP into its insoluble and aggregation-prone scrapie form (PrP) is the trigger for several rare devastating neurodegenerative disorders, collectively referred to as prion diseases. Recent work indicates that the ubiquitin-proteasome system is involved in quality control of PrP.
View Article and Find Full Text PDFNovel Compounds Identified by Structure-Based Prion Disease Drug Discovery Using In Silico Screening Delay the Progression of an Illness in Prion-Infected Mice.
Neurotherapeutics
October 2020
Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
The accumulation of abnormal prion protein (PrP) produced by the structure conversion of PrP (PrP) in the brain induces prion disease. Although the conversion process of the protein is still not fully elucidated, it has been known that the intramolecular chemical bridging in the most fragile pocket of PrP, known as the "hot spot," stabilizes the structure of PrP and inhibits the conversion process. Using our original structure-based drug discovery algorithm, we identified the low molecular weight compounds that predicted binding to the hot spot.
View Article and Find Full Text PDFVesicle-mediated secretion of misfolded prion protein molecules from cyclosporin A-treated cells.
FASEB J
March 2018
Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University School of Medicine, Jerusalem, Israel.
Loss of protein homeostasis is a hazardous situation that jeopardizes cellular functionality and viability. Cells have developed mechanisms that supervise protein integrity and direct misfolded molecules for degradation. Nevertheless, subsets of aggregation-prone proteins escape degradation and form aggregates that can underlie the development of neurodegenerative disorders.
View Article and Find Full Text PDFPrP-containing aggresomes are cytosolic components of an ER quality control mechanism.
J Cell Sci
October 2016
Biochemistry and Molecular Biology, the Institute for Medical Research Israel - Canada (IMRIC), the School of Medicine of the Hebrew University of Jerusalem, Jerusalem 91120, Israel
Limited detoxification capacity often directs aggregation-prone, potentially hazardous, misfolded proteins to be deposited in designated cytosolic compartments known as 'aggresomes'. The roles of aggresomes as cellular quality control centers, and the cellular origin of the deposits contained within these structures, remain to be characterized. Here, we utilized the observation that the prion protein (PrP, also known as PRNP) accumulates in aggresomes following the inhibition of folding chaperones, members of the cyclophilin family, to address these questions.
View Article and Find Full Text PDFStructure-Based Drug Discovery for Prion Disease Using a Novel Binding Simulation.
EBioMedicine
July 2016
Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Japan.
The accumulation of abnormal prion protein (PrP(Sc)) converted from the normal cellular isoform of PrP (PrP(C)) is assumed to induce pathogenesis in prion diseases. Therefore, drug discovery studies for these diseases have focused on the protein conversion process. We used a structure-based drug discovery algorithm (termed Nagasaki University Docking Engine: NUDE) that ran on an intensive supercomputer with a graphic-processing unit to identify several compounds with anti-prion effects.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!