One of the hallmarks of senescent cells is the senescence-associated secretory phenotype (SASP). The SASP-secretome is very well characterized, but the basis for the SASP is a rearrangement of the whole secretory pathway, indicated by morphological changes like dispersal of the Golgi, increase in lysosomal volume, increase in lysosomal lipofuscin aggregation and increased expression of the lysosomal enzyme b-galactosidase. Not surprisingly endoplasmatic reticulum (ER)-stress pathways including the UPR are up-regulated in senescent cells. Little is known about the molecular mechanisms mediating the rearrangement of the secretory pathway that ultimately results in SASP.
Specific aims of this project:
(1) To establish a comprehensive atlas of senescent-induced PTMs in the secretory pathway. (2) To mechanistically understand the impact on individual PTMs on proteins of the secretory pathway and their role in senescence and SASP-development. (3) To identify targets and prepare for screening assays for the development of future therapeutic interventions.
The anti-aging protein Klotho is strongly expressed in kidney and choroid plexus (CP). In kidney, full length Klotho functions as a co-receptor for FGF23. In addition, Klotho is shed from the surface and, together with a secreted splice form of Klotho, supplies the periphery with soluble Klotho (Klothos). In the CP, the function of Klotho is not known, but Klothos is a constituent of cerebrospinal fluid (CSF) produced by the CP. In mice and humans, Klotho is involved in cognitive performance and is down-regulated in ageing. Klotho is heavily glycosylated, which could affect its stability or activity. In our project, we want to test whether Klotho activity and/or stability is modulated by enzymatic and non-enzymatic PTM. We also analyse the role of Klotho in brain ageing using specific mouse knock-out models. Finally, we want to analyse the role of mammalian Klotho in IGF1/FOXO signalling and its modulation by PTMs.