Targeting SerpinE1 reverses cellular features of Hutchinson-Gilford progeria syndrome

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, fatal disease caused by Lamin A mutation, leading to altered nuclear architecture, loss of perinuclear heterochromatin and deregulated gene expression. HGPS patients eventually die by coronary artery disease and cardiovascular alterations. However, how deregulated transcriptional networks at the cellular level impact on the systemic disease phenotype is currently unclear. We have performed a longitudinal genome-wide analysis of gene expression in primary HGPS fibroblasts from patients at two sequential stages of disease that revealed a progressive activation of Rho signaling and SerpinE1, also known as Plasminogen Activator Inhibitor (PAI-1). siRNA-mediated downregulation or pharmacological inhibition of SerpinE1 by TM5441 could revert key pathological features of HGPS in patient-derived fibroblasts, including re-activation of cell cycle progression, reduced DNA damage signaling, decreased expression of pro-fibrotic genes and recovery of mitochondrial defects. These effects were accompanied by reduced levels of Progerin and correction of nuclear abnormalities. These data point to SerpinE1 as a novel potential effector of HGPS pathogenesis and target for therapeutic interventions.