Role of the nuclear envelope in regulation of ageing

Thesis

Cellular senescence is a phenomenon characterised by stable and durable states of proliferative arrest induced by various stress stimuli. The abundance of senescent cells in tissues increases over a lifetime and, among other functions, they have been proposed to play a pivotal role in ageing. Hutchinson-Gilford progeria syndrome (HGPS) is a disease characterised by segmental premature ageing. It is caused by the expression of a persistently farnesylated lamin A isoform. Strikingly, HGPS patients show an increased abundance of senescent cells. Therefore the relationship between the farnesylated lamin A precursor, prelamin A, and senescence was studied in this thesis.

Cellular models of ageing in human dermal fibroblasts were established. They relied on either replicative exhaustion or prelamin A accumulation. An unbiased genome-wide transcript analysis of the ageing models revealed that a significant part of the common senescence programme during cellular ageing can be replicated in young cells by accumulating prelamin A. The most prominent and overlapping expression changes were observed in pathways regulating inflammation, lipid metabolism and cholesterol homeostasis. Six genes, identified as underexpressed consistently across the studied ageing models, were tested functionally in the context of senescence regulation by prelamin A. The ability of prelamin A-accumulating cells to induce inflammation has also been demonstrated by multiplexed detection of secreted cytokines, chemokines and other factors. This confirms that a significant overlap between replicative and prelamin A-induced senescence exists not only at mRNA level changes, but is also observed at the level of secreted proteins. Finally, nuclear morphology was studied in the ageing models, with a particular interest in the formation of a nucleoplasmic reticulum. We identified NOGO/Reticulon-4 as a new protein involved in the process of NR formation, and also demonstrated that new NR channels require incorporation of newly synthesised lipid and protein components. The research presented in this thesis offers a new insight into a role of the prelamin A maturation process in senescence and ageing.

Authors: Drozdz, M

• DOI: 10.5287/ora-agnvaqgn0
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Reticulons; Senescence; SASP; Prelamin A; Nucleoplasmic Reticulum
• Subjects: Senescence; Laminopathies; Nuclear Envelope; Ageing