061 Premature aging in Cockayne syndrome due to a failure in ribosomal biogenesis?

Abstract

061 Premature aging in Cockayne syndrome due to a failure in ribosomal biogenesis? M Alupei, P esser, K Scharffetter-Kochanek and S Iben 1 University of Ulm, Ulm, Germany and 2 University of freiburg, Freiburg, Germany Cockayne syndrome (CS) is a progeroid disease characterized by growth failure, neurological degeneration, loss of subcutaneous fat and cachexia. The mutations of this polygenic disease inactivate a subbranch of the DNA-repair pathway nucleotide excision repair (NER), thus Cockayne syndrome is regarded as a DNA-repair disease. As the total loss of DNA repair by the NER in xeroderma pigmentosum does not lead to childhood degeneration, alternative functions of the CS proteins might account for the disease. One common alternative function of the Cockayne syndrome proteins is the key step in ribosomal biogenesis, transcription by RNA polymerase I in the nucleolus. We investigated the cellular consequences of a failure of RNA polymerase I transcription in CS-cells and discovered a circulus vitiosus repressing ribosomal biogenesis. A disturbed RNA polymerase I transcription gives rise to ribosomes with a low translational fidelity that produce misfolded proteins. Misfolded proteins provoke endoplasmic reticulum stress and an unfolded protein response that represses RNA polymerase I transcription. The oxidative hypersensitivity of Cockayne syndrome cells might be due to oxidation of misfolded proteins. The elevated apoptosis rate of CS cells after oxidative challenge can be overcome by pharmacological chaperones that dampen endoplasmic reticulum stress and the unfolded protein response. Pharmacological chaperones are restoring proper RNA polymerase I transcription by de-repression thus breaking the circulus vitiosus. This might be a treatment opportunity for children suffering from premature aging. Moreover, loss of proteostasis due to a reduced translational fidelity of ribosomes might be a mechanism contributing to aging and aging associated diseases in humans. 062 Stress perception impacts on clinical signs of skin ageing and modifies the epigenome R Pattinson, C Bundy, L Cordingley, S Kyle, W Yeung, G Beauchef, A Nkengne, A O’Callaghan, CE Griffiths and RE Watson 1 University of Manchester, Manchester, United Kingdom, 2 Laboratoire CLARINS, Pontoise, France and 3 Fios Genomics Ltd., Edinburgh, United Kingdom In this study we tested the commonly held assumption that stress affects the appearance of skin through the premature occurrence of clinical features of skin ageing (lines, wrinkles and dark under-eye circles). We recruited 84 healthy adult female volunteers (age range, 24 e 40 years; mean 30.7 4.7 years); each volunteer completed a comprehensive battery of psychological and sleep questionnaires (State-Trait Anxiety Inventory, Perceived Stress Score, Hospital Anxiety and Depression Scale, Pittsburgh sleep quality index [PSQI], Ford insomnia response to stress test [FIRST] and consensus sleep diary), clinical photography (VISIA-CR ) and provided a sample of whole blood for epigenetic analysis. Image analysis of clinical photographs allowed the objective quantification of wrinkles around the eye (eye bag and crow’s feet), the nasolabial fold and deep mid-forehead frown lines. Initial analysis correlated perceived stress with worse sleep patterns; those volunteers who perceived stress more keenly had significantly disturbed sleep as measured by PSQI and FIRST with reduced sleep efficiency (r1⁄4-0.22; P<0.05) and increased wakefulness after sleep onset (r1⁄40.32; P<0.01). In addition, sleep onset latency positively correlated with increased measures for nasolabial folds, frown lines and crow’s feet wrinkles (r1⁄4-0.47; p<0.01). We next stratified the volunteers on the basis of their stress perception response to identify extreme groups (high stress response, n1⁄412; low stress response, n1⁄412) for epigenetic analysis of whole blood. Using Infinium HumanMethylation450BeadChip, principal component analysis identified significant clustering of methylation signatures between the two groups, with 484 differentially methylated regions observed (P<0.001). Hence, how an individual perceives psychological stress appears to impact on physical signs of skin ageing although the precise mechanism remains unclear.