Loss of Proteostasis Is a Pathomechanism in Cockayne Syndrome
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
Affiliations
Marius Costel Alupei
Clinic of Dermatology and Allergic Diseases, University Medical Center, Albert-Einstein Allee 23, 89081 Ulm, Germany
Pallab Maity
Clinic of Dermatology and Allergic Diseases, University Medical Center, Albert-Einstein Allee 23, 89081 Ulm, Germany
Philipp Ralf Esser
Allergy Research Group, Department of Dermatology, University Medical Center Freiburg, Faculty of Medicine, 79104 Freiburg, Germany
Ioanna Krikki
Clinic of Dermatology and Allergic Diseases, University Medical Center, Albert-Einstein Allee 23, 89081 Ulm, Germany
Francesca Tuorto
Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, 69120 Heidelberg, Germany
Rosanna Parlato
Institute of Applied Physiology, Ulm University, 89081 Ulm, Germany; Institute of Anatomy and Medical Cell Biology, Heidelberg University, 69120 Heidelberg, Germany
Marianna Penzo
Laboratorio di Patologia Clinica, Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Via Massarenti 9, 40138 Bologna, Italy
Adrian Schelling
Clinic of Dermatology and Allergic Diseases, University Medical Center, Albert-Einstein Allee 23, 89081 Ulm, Germany
Vincent Laugel
Laboratoire de Génétique Médicale - INSERM U1112, Institut de Génétique Médicale d’Alsace (IGMA), Faculté de médecine de Strasbourg, 11 rue Humann, 67000 Strasbourg, France
Lorenzo Montanaro
Laboratorio di Patologia Clinica, Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Via Massarenti 9, 40138 Bologna, Italy
Karin Scharffetter-Kochanek
Clinic of Dermatology and Allergic Diseases, University Medical Center, Albert-Einstein Allee 23, 89081 Ulm, Germany
Sebastian Iben
Clinic of Dermatology and Allergic Diseases, University Medical Center, Albert-Einstein Allee 23, 89081 Ulm, Germany; Corresponding author
Summary: 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. : Cockayne syndrome is a devastating childhood progeria. Here, Alupei et al. show that cells from CS patients have reduced translation accuracy and elevated ROS, leading to generation of unstable proteins and activation of ER stress. Reducing ER stress by chemical chaperones in these cells rescues RNA polymerase I activity and protein synthesis. Keywords: Cockayne syndrome, RNA polymerase I, translation fidelity, ER stress, unfolded protein response