Background and previous work
“Many phenomena that basic research tries to explain would simply be unknown had they not been uncovered by the study of diseases”. This statement from Vogel and Motulsky is also valid with respect to protein modifications in both “normal” and premature ageing, such as Hutchinson-Gilford Progeria. Most progeria patients carry a specific lamin A/C mutation, which results in truncated protein (progerin), lacking the site essential for cleaving a farnesyl group. Incompletely modified lamins accumulate at the nuclear membrane. The same lamin modifications are also found in cells of normally aged humans. Further, lamins are non-enzymatically modified by MGO, a precursor in the formation of AGEs. These lamin modifications increase with age and might cause vascular dysfunction and atherosclerosis. Amongst others, lamins bind to the lamin B receptor (LBR). LBR has sterol reductase activity and modifies chromatin. We previously showed that LBR-deficiency results in hyposegmented neutrophil nuclei, altered chromatin structure and variable phenotypes from skeletal deformities to neonatal death. We found that Lbr–/– mice resemble progerin mice, e.g. displaying alopecia. Furthermore, our preliminary experiments revealed early aged immune cells and altered AGEs in Lbr–/– mice.
The project aims to reveal and characterise molecular mechanisms and protein
modifications underlying the observed ageing phenomena in the mouse model and to test its relevance for the human ageing process. We will study in Lbr-deficient mice (1) whether age effects are caused by altered lamin farnesylation, (2) how they are associated with MGO-modifications, (3) which modifications of histones and lamins contribute to altered chromatin structure and transcription, and (4) how LBR interaction partners are themselves modified in ageing.
We will primarily study the above aspects in Lbr-deficient mice and will confirm results in mice expressing truncated lamin. In addition, we will study the protein modifications also in blood, lymphoblastoid cells, and fibroblasts from human patients, age matched controls and normally aged humans. We will provide these samples, as ageing models, also to other RTG groups. We will continue collaborating with SP8 on time- and tissue-dependent glycation in Lbr-deficient mice, with SP3 on protein polyubiquitination and transcription profiling as well as with SP5 on protein alterations of Lbr–/– immune cells. Further, we will collaborate with SP13 on vascular ageing and will provide Lbr-deficient mouse tissue samples. The project will contribute to the identification and characterisation of lamin network modifications in normal and premature ageing.