Abstract
Cockayne syndrome (CS) is a developmental disorder with symptoms that are typical for the aging body, including subcutaneous fat loss, alopecia, and cataracts. Here, we show that in the cells of CS patients, RNA polymerase I transcription and the processing of the pre-rRNA are disturbed, leading to an accumulation of the 18S-E intermediate. The mature 18S rRNA level is reduced, and isolated ribosomes lack specific ribosomal proteins of the small 40S subunit. Ribosomal proteins are susceptible to unfolding and the CS cell proteome is heat-sensitive, indicating misfolded proteins and an error-prone translation process in CS cells. Pharmaceutical chaperones restored impaired cellular proliferation. Therefore, we provide evidence for severe protein synthesis malfunction, which together with a loss of proteostasis constitutes the underlying pathophysiology in CS.
Highlights
Cockayne syndrome (CS) is a rare premature aging disease characterized by childhood onset of degenerative symptoms reminiscent of the aging body, including subcutaneous fat loss, alopecia, cataracts, neurological degeneration, and cachexia [1]
The primers used to amplify the unprocessed 47S precursor bind the 50 external transcribed spacer that is cleaved in the first processing step A’
Initiation and elongation are differentially regulated in RNA polymerase I transcription [20]
Summary
Cockayne syndrome (CS) is a rare premature aging disease characterized by childhood onset of degenerative symptoms reminiscent of the aging body, including subcutaneous fat loss, alopecia, cataracts, neurological degeneration, and cachexia [1]. These symptoms are accompanied by developmental delay, resulting in a severe phenotype that can lead to childhood mortality. A homozygous null mutation in CSB was identified in a UV-sensitive (UVs) patient that displayed TCR failure, which is the common hallmark of CS. The total loss of NER is not followed by degenerative features during childhood, suggesting that alternative functions of the CS proteins play a crucial role in the disease pathogenesis [5]
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