Researchers at the Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, have uncovered how a protein known as lamin A assists in repairing the protective barrier surrounding a cell's DNA. This research has significant implications for treating Hutchinson-Gilford Progeria Syndrome, a rare condition that leads to premature aging.
The nuclear envelope (NE) serves as a crucial barrier safeguarding the cell's genetic material, supported by the nuclear lamina (NL), a fibrous network of proteins including lamin A (LA) and lamin C (LC). When mechanical stress or genetic mutations occur, ruptures in the NE can expose genetic material to damage. While lamin C quickly accumulates at these rupture sites to facilitate repair, lamin A shows a slower and less effective localization.
This delayed response is particularly problematic in conditions like Hutchinson-Gilford Progeria Syndrome (HGPS). A mutation in the LMNA gene produces progerin, a defective form of lamin A that remains permanently associated with the NE, impairing repair mechanisms. Progerin's reduced mobility limits the available pool of lamin A for repair, exacerbating cellular damage and accelerating aging symptoms in affected individuals.
An international research team led by Takeshi Shimi sought to determine why lamin A localizes more slowly to NE rupture sites compared to lamin C. They focused on how lamin A's unique tail region and post-translational modifications, such as farnesylation, affect its localization and function.
Key findings include the identification of specific sequences in lamin A's tail region, termed 'Lamin A-Characteristic Sequences' (LACS1 and LACS2), which inhibit rapid localization to rupture sites. Additionally, progerin's defective structure results in its permanent retention at the NE, diminishing the nucleoplasmic pool of lamin A necessary for efficient NE repair. This delayed response contributes to nuclear instability and cellular aging.
The study also explored therapeutic potential. A farnesyltransferase inhibitor (FTI), lonafarnib (Zokinvy), was found to improve the mobility of progerin and lamin A, increasing their nucleoplasmic availability and significantly enhancing NE repair in both healthy and HGPS models. This drug is approved for treating patients with HGPS in the United States, Europe, and Japan.
The authors stated, 'This study bridges a critical gap in our understanding of Lamin A's role in nuclear repair. It provides actionable insights for developing therapies targeting conditions where nuclear instability is a hallmark, such as HGPS.'