UCLA

Children with Hutchinson-Gilford progeria syndrome (HGPS) display symptoms resembling accelerated aging, with most succumbing in their mid-teens to complications from arteriosclerotic lesions in major arteries. HGPS arises from a de novo mutation in the LMNA gene, such as the Gly608Gly mutation, which creates an aberrant splice donor site, resulting in a deletion of 50 amino acids in prelamin A and the production of mutant protein called progerin. Progerin, unlike mature lamin A, retains a farnesyl lipid anchor, which contributes to cellular toxicity. In HGPS, a prominent vascular anomaly is reduced numbers of smooth muscle cells (SMCs) in the medial layer of large arteries, promoting arteriosclerotic disease. In order to study the underlying mechanisms of vascular disease in HGPS, we created a mouse model of HGPS (LmnaG609G) which exhibits disease phenotypes reminiscent of human HGPS, including the hallmark vascular disease. We also created an in vitro doxycycline-inducible cell culture system to investigate properties of progerin by studying the effects of progerin on the nuclear lamina meshwork, nuclear mechanics, integrity of the nuclear envelope, their relationship to nuclear morphology, DNA damage, and cell viability. In this dissertation, my goal was to understand the mechanisms underlying vascular pathology in HGPS, focusing on the interactions between progerin, lamin B1, and the integrity of the nuclear lamina meshwork in vascular SMCs. In Chapter 2, we investigated the role of mechanical stress on the vascular disease and showed that disrupting the LINC complex in smooth muscle cells reduces SMC loss in LmnaG609G mice. In Chapter 3, we hypothesized that progerin weakens the structural integrity of the nuclear envelope. Indeed, we showed that progerin resulted in nuclear membrane ruptures and found that it was responsible for vascular pathology in vivo. In Chapter 4, we investigated a more fundamental question—how does progerin induce abnormal biological effects in cells? We discovered that progerin forms an abnormal meshwork, characterized by clusters of large meshwork gaps. Unexpectedly, progerin had a dominant-negative effect on the nuclear lamina, thus further disrupting nuclear integrity. In Chapter 5, I summarize our key findings and discuss our current view on the mechanisms of vascular smooth muscle cell loss in HGPS.