Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria

Abstract

Hutchinson-Gilford progeria (HGPS) is a premature ageing syndrome caused by a mutation in LMNA, resulting in a truncated form of lamin A called progerin. Progerin triggers loss of the heterochromatic marker H3K27me3, and premature senescence, which is prevented by telomerase. However, the mechanism how progerin causes disease remains unclear. Here, we describe an inducible cellular system to model HGPS and find that LAP2α (lamina-associated polypeptide-α) interacts with lamin A, while its interaction with progerin is significantly reduced. Super-resolution microscopy revealed that over 50% of telomeres localize to the lamina and that LAP2α association with telomeres is impaired in HGPS. This impaired interaction is central to HGPS since increasing LAP2α levels rescues progerin-induced proliferation defects and loss of H3K27me3, whereas lowering LAP2 levels exacerbates progerin-induced defects. These findings provide novel insights into the pathophysiology underlying HGPS, and how the nuclear lamina regulates proliferation and chromatin organization.DOI: http://dx.doi.org/10.7554/eLife.07759.001

Disrupting the LINC complex in smooth muscle cells reduces aortic disease in a mouse model of Hutchinson-Gilford progeria syndrome

“…In cultured cells, increased amounts of progerin result in more misshapen nuclei, more DNA damage, and more rapid senescence (18, 30). In mouse models, the severity of disease expression correlates with levels of progerin expression (32, 33, 35) (Fig.…”

Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations

“…These nuclear defects are exacerbated during proliferation in culture, concomitant with accumulation of progerin and immobilization of lamin A at the nuclear lamina. Recent studies have shown a dosage-dependent effect of progerin expression in normal fibroblasts inducing phenotypes characteristic of HGPS fibroblasts (Chojnowski, Ong et al 2015). This suggests that reducing progerin levels under a threshold could be sufficient to reduce phenotype severity.…”

“…In contrast, progerin interacts weakly with LAP2α, and expression of progerin reduces dramatically the cellular levels of LAP2α (Vidak, Kubben et al 2015). This is accompanied by reduced H3K27me3 levels and proliferation defects, which are rescued by increasing LAP2α levels (Chojnowski, Ong et al 2015, Vidak, Kubben et al 2015). Barrier-to-Autointegration Factor (BAF) is another lamina-associated protein recently proposed to mediate chromatin defects upon expression of prelamin A/progerin (Loi, Cenni et al 2015).…”

“…Importantly, telomerase expression also reverts progerin-induced changes in gene expression. In particular, many deregulated genes in progerin-expressing cells are linked to senescence, and telomerase can rescue the majority of these changes (Chojnowski, Ong et al 2015). In addition, this study demonstrated that embryonic stem cells (ESCs), which express high levels of telomerase, are protected from progerin-induced phenotypes.…”

Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases

“…Although TERT expression in fibroblasts from patients with HGPS can rescue certain cellular ageing-associated defects, the observation that progerin and TERT-expressing human fibroblasts retain some ageing defects suggests that other cellular ageing mechanisms may either regulate the integrity of telomeres and other genomic regions or drive ageing 32,74 .…”