Marie Skłodowska-Curie Postdoctoral Fellowship for Lung Yu Liang

Mechanistic understanding towards how progerin contributes to premature ageing

The Marie Skłodowska-Curie Actions of the European Union support the career of talented early career researchers who move abroad to gain experience in other countries and fosters excellence in science. Liang was among the 15.8 % of applicants who were gruanted in 2024.

Objective

The nuclear lamina is a meshwork of lamin proteins that underlie the inner nuclear membrane and confer mechanical stability to the nuclear envelope. Mutations in lamins are associated with many disorders, including Progeria, a fatal premature ageing disease. In progeroid cells, expression of a truncated form of lamin A, named progerin, drastically deforms the nuclear envelope, causing premature cellular senescence. However, the underlying molecular mechanisms remain unclear. The nuclear pore complexes (NPCs) enable selective transport across the nuclear envelope. The diameter of the NPC central channel and the resulting nucleocytoplasmic exchange is governed by membrane tension, which is predicted to alter in the progeroid nuclei. Therefore, a theory is postulated that the structural integrity of the NPCs is disrupted in progeroid cells, as a result of the deformed nuclear envelope, and/or direct interaction with progerin. This may lead to further deregulation of nuclear transport that potentially drives cellular senescence.The project aims to investigate whether the NPCs indeed undergo compositional and conformational change in Progeria patient-derived primary cells, and to what extent nuclear transport is impacted. In cellulo cryo-electron tomography will be applied to unveil the molecular organisation of the progeroid NPCs. Further fluorescence microscopy-based cellular assays will be employed to identify proteins with nucleocytoplasmic mislocalisation.