General loss of proteostasis links Huntington disease to Cockayne syndrome.

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.

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Copyright © 2024. Published by Elsevier Inc.

Déclaration de conflit d'intérêts

Declaration of competing interest G.B.L. has provided consulting services, advisory board functions, clinical trial services and/or lectures for Acadia Pharmaceuticals, Affiris, Allergan, Alnylam, Amarin, AOP Orphan Pharmaceuticals AG, Bayer Pharma AG, Boehringer-Ingelheim, CHDI-Foundation, Deutsche Huntington-Hilfe, Desitin, Genentech, Genzyme, GlaxoSmithKline, F. Hoffmann-LaRoche, Ipsen, ISIS Pharma (IONIS), Lilly, Lundbeck, Medesis, Medivation, Medtronic, NeuraMetrix, Neurosearch Inc., Novartis, Pfizer, Prana Biotechnology, Prilenia, PTC Therapeutics, Raptor, Remix Therapeutics, Rhône-Poulenc Rorer, Roche Pharma AG Deutschland, Sage Therapeutics, Sanofi-Aventis, Sangamo/Shire, Siena Biotech, Takeda, Temmler Pharma GmbH, Teva, Triplet Therapeutics, Trophos, UniQure and Wave Life Sciences. The other authors declare no conflict of interests.