Loss of Proteostasis Is a Pathomechanism in Cockayne Syndrome
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 polymera...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-05-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718305850 |
| _version_ | 1819078791408910336 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Marius Costel Alupei |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-12-21T19:18:42Z |
| format | Article |
| id | doaj.art-98f1ad7eb84b485e8b920342542da1cf |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-21T19:18:42Z |
| publishDate | 2018-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-98f1ad7eb84b485e8b920342542da1cf2022-12-21T18:53:00ZengElsevierCell Reports2211-12472018-05-0123616121619Loss of Proteostasis Is a Pathomechanism in Cockayne SyndromeMarius Costel Alupei0Pallab Maity1Philipp Ralf Esser2Ioanna Krikki3Francesca Tuorto4Rosanna Parlato5Marianna Penzo6Adrian Schelling7Vincent Laugel8Lorenzo Montanaro9Karin Scharffetter-Kochanek10Sebastian Iben11Clinic of Dermatology and Allergic Diseases, University Medical Center, Albert-Einstein Allee 23, 89081 Ulm, GermanyClinic of Dermatology and Allergic Diseases, University Medical Center, Albert-Einstein Allee 23, 89081 Ulm, GermanyAllergy Research Group, Department of Dermatology, University Medical Center Freiburg, Faculty of Medicine, 79104 Freiburg, GermanyClinic of Dermatology and Allergic Diseases, University Medical Center, Albert-Einstein Allee 23, 89081 Ulm, GermanyDivision of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, 69120 Heidelberg, GermanyInstitute of Applied Physiology, Ulm University, 89081 Ulm, Germany; Institute of Anatomy and Medical Cell Biology, Heidelberg University, 69120 Heidelberg, GermanyLaboratorio di Patologia Clinica, Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Via Massarenti 9, 40138 Bologna, ItalyClinic of Dermatology and Allergic Diseases, University Medical Center, Albert-Einstein Allee 23, 89081 Ulm, GermanyLaboratoire de Génétique Médicale - INSERM U1112, Institut de Génétique Médicale d’Alsace (IGMA), Faculté de médecine de Strasbourg, 11 rue Humann, 67000 Strasbourg, FranceLaboratorio di Patologia Clinica, Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Via Massarenti 9, 40138 Bologna, ItalyClinic of Dermatology and Allergic Diseases, University Medical Center, Albert-Einstein Allee 23, 89081 Ulm, GermanyClinic of Dermatology and Allergic Diseases, University Medical Center, Albert-Einstein Allee 23, 89081 Ulm, Germany; Corresponding authorSummary: 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 responsehttp://www.sciencedirect.com/science/article/pii/S2211124718305850 |
| spellingShingle | 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 Loss of Proteostasis Is a Pathomechanism in Cockayne Syndrome Cell Reports |
| title | Loss of Proteostasis Is a Pathomechanism in Cockayne Syndrome |
| title_full | Loss of Proteostasis Is a Pathomechanism in Cockayne Syndrome |
| title_fullStr | Loss of Proteostasis Is a Pathomechanism in Cockayne Syndrome |
| title_full_unstemmed | Loss of Proteostasis Is a Pathomechanism in Cockayne Syndrome |
| title_short | Loss of Proteostasis Is a Pathomechanism in Cockayne Syndrome |
| title_sort | loss of proteostasis is a pathomechanism in cockayne syndrome |
| url | http://www.sciencedirect.com/science/article/pii/S2211124718305850 |
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