Loss of Proteostasis Is a Pathomechanism in Cockayne Syndrome.

Abstract

Retarded growth and neurodegeneration are hallmarks of the premature aging disease Cockayne syndrome (CS). Cockayne syndrome proteins take part in the key step of ribosomal biogenesis, transcription of RNA polymerase I. Here, we identify a mechanism originating from a disturbed RNA polymerase I transcription that impacts translational fidelity of the ribosomes and consequently produces misfolded proteins. In cells from CS patients, the misfolded proteins are oxidized by the elevated reactive oxygen species (ROS) and provoke an unfolded protein response that represses RNA polymerase I transcription. This pathomechanism can be disrupted by the addition of pharmacological chaperones, suggesting a treatment strategy for CS. Additionally, this loss of proteostasis was not observed in mouse models of CS.

• Authors: Marius Costel Alupei, Pallab Maity, Philipp Ralf Esser, Ioanna Krikki, Francesca Tuorto, Rosanna Parlato, Marianna Penzo, Adrian Schelling, Vincent Laugel, Lorenzo Montanaro, Karin Scharffetter-Kochanek, Sebastian Iben
• Journal: Cell reports (Cell Rep) Vol. 23 Issue 6 Pg. 1612-1619 (05 08 2018) ISSN: 2211-1247 [Electronic] United States
• PMID: 29742419 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Reactive Oxygen Species
• RNA Polymerase I

Topics

• Animals
• Cell Line
• Cockayne Syndrome (genetics, pathology)
• Endoplasmic Reticulum Stress
• Humans
• Mice
• Mutation (genetics)
• Oxidative Stress
• Protein Biosynthesis
• Protein Folding
• Proteostasis
• RNA Polymerase I (genetics)
• Reactive Oxygen Species (metabolism)
• Transcription, Genetic
• Xeroderma Pigmentosum (genetics, pathology)