Cockayne syndrome (CS) is a childhood disorder of developmental delay, degeneration and signs of premature aging. Neurological degeneration is one hallmark of the disease. Using patient skin fibroblasts, we could describe a novel pathomechanism in CS, ribosomal dysfunction leading to a loss of protein homeostasis. As loss of proteostasis characterizes most aging-associated neurological diseases, we asked if ribosomal dysfunction may contribute to the development of these disorders. By RNA-sequencing and analysis we defined the gene expression signature of CS patient skin cells and compared it to published gene expression signatures of neurological disorders. Amongst others, Huntington`s disease (HD) gene expression patterns matched with CS. Huntington is a dominant inherited, fatal late-onset disease of striatal neurodegeneration, characterized by choreatic movements, sarcopenia and personality disorders. The molecular pathomechanism of HD is unknown and here we propose a novel hypothesis. We can show that gene expression patterns derived from CS can discriminate HD from healthy controls to 100%. ChIP analysis revealed that huntingtin, the protein whose mutation causes HD, binds to the rDNA, encoding for the rRNA backbone of the ribosome. Pre-rRNA synthesis and processing is disturbed in cells of HD patients. The accuracy of the translation at the ribosome is reduced, leading to misfolded proteins that are carbonylated by the elevated reactive oxygen species (ROS) in HD cells. The striking similarities between a childhood disorder of premature aging and an aging-associated disease validates CS as a model for aging research and justifies research on rare diseases.

ESDR280 - Research on skin cells unravels general mechanisms of neurological degeneration

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.