Targeting the phospholipase A2 receptor ameliorates premature aging phenotypes.

Audrey Griveau,David Bernard,Dorian V Ziegler,Benjamin Le Calvé,David Vindrieux,Nadine Martin,Martin O Bergo,Marine Warnier,Sophia Djebali,Clotilde Wiel,Jacqueline Marvel

doi:10.1111/acel.12835

Abstract

Hutchinson–Gilford progeria syndrome (HGPS) is a lethal premature aging that recapitulates many normal aging characteristics. This disorder is caused by mutation in the LMNA gene leading to the production of progerin which induces misshapen nuclei, cellular senescence, and aging. We previously showed that the phospholipase A2 receptor (PLA2R1) promotes senescence induced by replicative, oxidative, and oncogenic stress but its role during progerin‐induced senescence and in progeria is currently unknown. Here, we show that knockdown of PLA2R1 prevented senescence induced by progerin expression in human fibroblasts and markedly delayed senescence of HGPS patient‐derived fibroblasts. Whole‐body knockout of Pla2r1 in a mouse model of progeria decreased some premature aging phenotypes, such as rib fracture and decreased bone content, together with decreased senescence marker. Progerin‐expressing human fibroblasts exhibited a high frequency of misshapen nuclei and increased farnesyl diphosphate synthase (FDPS) expression compared to controls; knockdown of PLA2R1 reduced the frequency of misshapen nuclei and normalized FDPS expression. Pamidronate, a FDPS inhibitor, also reduced senescence and misshapen nuclei. Downstream of PLA2R1, we found that p53 mediated the progerin‐induced increase in FDPS expression and in misshapen nuclei. These results suggest that PLA2R1 mediates key premature aging phenotypes through a p53/FDPS pathway and might be a new therapeutic target.

Highlights

The LMNA gene encodes lamin A and C proteins, which are located in the nuclear lamina where they contribute to rigidity and shape of the nuclear envelope and regulate chromatin organization and gene expression
We found that phospholipase A2 receptor 1 (PLA2R1) mediates effects of progerin expression on cellular senescence and some premature aging hallmarks
Because PLA2R1 participates in senescence induced by short telomeres, oncogene, and oxidative stress, the current results reinforce the concept that PLA2R1 is a master regulator of cellular senescence (Augert et al, 2009; Bernard, & Vindrieux, 2014; Vindrieux et al, 2013)

Summary

| INTRODUCTION

The LMNA gene encodes lamin A and C proteins, which are located in the nuclear lamina where they contribute to rigidity and shape of the nuclear envelope and regulate chromatin organization and gene. PLA2R1 encodes a transmembrane protein that can bind to secreted phospholipase A2 (sPLA2) and some collagen and integrin isoforms; and may regulate cellular senescence through the activation of JAK/STAT signaling and the ERRα transcription factor (Augert et al, 2009, 2013; Bernard, & Vindrieux, 2014; Griveau et al, 2016; Vindrieux et al, 2013; Vindrieux et al, 2013). These results raise the interesting question of whether PLA2R1 may contribute to premature aging.

| RESULTS

| DISCUSSION

Findings

| MATERIALS AND METHODS