The cell matrix connection to premature ageing

The nuclei of cells are directly linked to their extracellular environment via a bridge which encompasses focal adhesions, the actin cytoskeleton and the LINC complex. This bridge can act as a conduit via which extracellular forces are channelled to the nuclear interior and the Lamin A/C nucleo-cytoskeletal network, triggering changes in cellular behaviour and transcription. Hutchinson-Gilford Progeria Syndrome (HGPS) is a degenerative premature ageing disease resulting from de novo point mutations within the LMNA gene that cause an alternate transcript called progerin to be translated. Progerin expression affects nuclear morphology and is known to inhibit nuclear import/export of proteins through clustering of nuclear pore complexes. Defects in nuclear import/export have been shown to be causative of the cellular phenotypes seen in HGPS (Larrieu et al. Science 344(6183):527-32 (2014)). Ageing cell nuclei show similarities with HGPS nuclei for unknown reasons, possibly through a slow enrichment of Progerin over time. Comparison of cells within a 2- and 3-D matrix context demonstrated that the nuclei of cells within a 3-D environment experience greater tension than those within a 2-D environment. Overexpression of wildtype Lamin A/C and Progerin has shown that Progerin expressing cells show less nuclear force coupling (via Nesprin-2 based tension sensor), as well as reduced tension at focal adhesions (via a Talin-tension sensor). This project will investigate how the altered nucleo-cytoskeletal architecture in ageing cells and HGPS affects cell matrix adhesions and leads to nuclear import defects that cause HGPS symptoms. We will investigate this question in two separate but connected work packages (WP) to mitigate risk for the student.
Aims:
WP1: Investigate effect of impaired nuclear force coupling on matrix adhesion dynamics and composition.
WP2: Interrogate effect of matrix adhesion complexes on nuclear pore complex function and nuclear protein import/export.