Endoplasmic reticulum stress at the crossroads of progeria and atherosclerosis

Abstract

Hutchinson–Gilford progeria syndrome (HGPS) is a rare pathology caused by a specific mutation (c.1824C>T; p.G608G) in the LMNA gene (Eriksson et al, 2003). In healthy conditions, LMNA encodes lamins A and C, two major structural nuclear proteins. The mutation creates a splice site in exon 11, resulting in ubiquitous expression of progerin, an aberrant lamin A precursor. Mutations of LMNA can cause laminopathies, a group of diseases with a wide spectrum of, often overlapping, tissue‐specific phenotypes. HGPS is probably one of the most devastating forms of laminopathy. Affected patients display signs of accelerated aging, such as lack of subcutaneous fat, hair loss, joint contractures, and skin thinning, and usually die prematurely from cardiovascular complications. Atherosclerosis is one of the most severe and clinically relevant features of HGPS, manifesting in the absence of classical risk factors, such as increased low‐density lipoprotein and C‐reactive protein (Gordon et al, 2005). In this issue, Hamczyk et al (2019) describe a mechanism for HGPS‐related atherosclerosis.

Figure 1. Mechanisms of VSMC loss in HGPS‐dependent atherosclerosis

(A) State of the art of cellular and molecular mechanisms taking place in HGPS‐VSMCs from animal models and patients (either primary or iPSC‐derived cells). Nuclear structural defects (1), accumulation of progerin (2), transcriptional changes due to chromatin remodeling (3), and increased DNA damage (4) are the “classical” hallmarks of progeric cells. In addition, activation of the NRF2 pathway and oxidative stress are associated with HGPS. (B) New molecular insights from the work published in this issue, demonstrating that the ER stress response and activation of the UPR play major roles in VSMC death and atherosclerosis in mice with VSMC‐restricted progerin expression. Administration of the chemical chaperone tauroursodeoxycholic acid (TUDCA) is sufficient to rescue cell homeostasis, reduce atherosclerosis progression, and improve lifespan.