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Loss of proteostasis is a pathomechanism in Cockayne syndrome

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 tran...

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Main Authors: Alupei, Marius-Costel (Author) , Maity, Pallab (Author) , Esser, Philipp Ralf (Author) , Krikki, Ioanna (Author) , Tuorto, Francesca (Author) , Parlato, Rosanna (Author) , Penzo, Marianna (Author) , Schelling, Adrian (Author) , Laugel, Vincent (Author) , Montanaro, Lorenzo (Author) , Scharffetter-Kochanek, Karin (Author) , Iben, Sebastian (Author)
Format: Article (Journal)
Language:English
Published: May 8, 2018
In: Cell reports
Year: 2018, Volume: 23, Issue: 6, Pages: 1612-1619
ISSN:2211-1247
DOI:10.1016/j.celrep.2018.04.041
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.celrep.2018.04.041
Verlag, lizenzpflichtig, Volltext: http://www.sciencedirect.com/science/article/pii/S2211124718305850
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Author Notes: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, and Sebastian Iben
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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.
Item Description:Gesehen am 11.05.2020
Physical Description:Online Resource
ISSN:2211-1247
DOI:10.1016/j.celrep.2018.04.041

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