IS THE PROLINE METABOLIC PATHWAY DRIVING HUMAN SKIN AGEING?

Abstract

De Barsy syndrome is a recessive progeroid disease belonging to the group of cutis laxa syndromes. PYCR1 or P5CS loss-of-function mutations are responsible for this disease with prominent progeroid skin. Here, I report five PYCR1 pathogenic alleles and establish a mouse knockout model that phenocopies the patients’ anomalies. This mouse model together with the patients’ phenotype confirms the requirement of PYCR1 for youthful skin. In addition, I identify telomere attrition as a potential link between PYCR1 and loss of proliferative capacity in patient cultured cells. Lastly, I show in vitro and in vivo that senescence and chronological aging are accompanied by low protein levels of PYCR1, even if forced PYCR1 does not alleviate senescence in vitro. Collectively my findings establish PYCR1 not only as a driver, but also as a novel marker of aging and provide insights on potential therapeutic approaches to mitigate the effects of aging on connective tissues.