General loss of proteostasis links Huntington disease to Cockayne syndrome

• Published in: Neurobiology of disease Vol. 201; p. 106668
• Main Authors: Wagner, Maximilian, Zhu, Gaojie, Khalid, Fatima, Phan, Tamara, Maity, Pallab, Lupu, Ludmila, Agyeman-Duah, Eric, Wiese, Sebastian, Lindenberg, Katrin S., Schön, Michael, Landwehrmeyer, G. Bernhard, Penzo, Marianna, Kochanek, Stefan, Scharffetter-Kochanek, Karin, Mulaw, Medhanie, Iben, Sebastian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.10.2024; Elsevier
• Subjects: Cockayne syndrome; Huntington disease; Loss of proteostasis; Protein carbonylation; Ribosome; Cockayne syndrome; Loss of proteostasis; Protein carbonylation; Ribosome; Huntington disease
• ISSN: 0969-9961; 1095-953X; 1095-953X
• DOI: 10.1016/j.nbd.2024.106668

Cockayne syndrome (CS) is an autosomal recessive disorder of developmental delay, multiple organ system degeneration and signs of premature ageing. We show here, using the RNA-seq data from two CS mutant cell lines, that the CS key transcriptional signature displays significant enrichment of neurodegeneration terms, including genes relevant in Huntington disease (HD). By using deep learning approaches and two published RNA-Seq datasets, the CS transcriptional signature highly significantly classified and predicted HD and control samples. Neurodegeneration is one hallmark of CS disease, and fibroblasts from CS patients with different causative mutations display disturbed ribosomal biogenesis and a consecutive loss of protein homeostasis - proteostasis. Encouraged by the transcriptomic data, we asked whether this pathomechanism is also active in HD. In different HD cell-culture models, we showed that mutant Huntingtin impacts ribosomal biogenesis and function. This led to an error-prone protein synthesis and, as shown in different mouse models and human tissue, whole proteome instability, and a general loss of proteostasis. [Display omitted] •Cockayne syndrome transcriptomic patterns include Huntington disease signatures.•Cockayne syndrome transcriptomic patterns can predict Huntington disease.•Huntingtin is part of ribosomal biogenesis.•Mutant Huntingtin affects ribosomal translational accuracy.•Whole proteome instability characterizes HD cells, mouse models and patient tissue.