Targeting the phospholipase A2 receptor ameliorates premature aging phenotypes

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.

The JAK1/2 inhibitor ruxolitinib delays premature aging phenotypes

“…Consistently, the JAK/STAT pathway drives the cell cycle arrest associated with PLA2R1‐induced senescence, thus affecting senescence beyond the sole inhibition of the SASP as described by others (Farr et al, ; Xu et al, , ) or/and because the SASP can be also a critical mediator of the full senescence (Acosta et al, ). Moreover, we recently observed that PLA2R1 contributes to progeria phenotypes in vitro in progerin‐expressing cells and in vivo in the Zmpste24 −/− murine model of progeria (Griveau et al, ).…”

“…However, little is known about the role of this protein and of these interactions. PLA2R1 promotes cellular senescence in different contexts, and JAK/STAT signaling mediates the pro‐senescent effects of PLA2R1 (Augert et al, ; Bernard & Vindrieux, ; Griveau et al, ; Vindrieux et al, ). Consistently, the JAK/STAT pathway drives the cell cycle arrest associated with PLA2R1‐induced senescence, thus affecting senescence beyond the sole inhibition of the SASP as described by others (Farr et al, ; Xu et al, , ) or/and because the SASP can be also a critical mediator of the full senescence (Acosta et al, ).…”

“…To define the ability of ruxolitinib to influence progerin‐induced senescence, we used normal human fibroblasts (MRC5) constitutively expressing progerin or control cells expressing lamin A (Griveau et al, ). The expression of progerin strongly inhibited cell proliferation when compared to lamin A‐expressing cells (Figure a,b).…”

“…Earlier studies revealed that PLA2R1 contributes to progerin‐induced senescence by stimulating farnesyl diphosphate synthase (FDPS) expression and misshapen nuclei formation (Augert et al, ; Griveau et al, ; Vindrieux et al, ). FDPS controls the production of a farnesyl lipid, which is attached to the carboxyl terminus of progerin and which is required for its ability to cause disease and induce the characteristic nuclear shape abnormalities observed in HGPS cells (Varela et al, ).…”

“…The effect of ruxolitinib on progeria phenotypes is a phenocopy of that observed in Pla2r1 knockout mice, that is, reduced numbers of rib fractures, increased BMC, and improved grip strength (Griveau et al, ). Moreover, similar to Pla2r1 −/− mice, ruxolitinib did not affect body weight or bone mineral density (BMD) (Figure a,b).…”