Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation

Abstract

Zmpste24 (also called FACE-1) is a metalloproteinase involved in the maturation of lamin A (Lmna), an essential component of the nuclear envelope. Both Zmpste24- and Lmna-deficient mice exhibit profound nuclear architecture abnormalities and multiple histopathological defects that phenocopy an accelerated ageing process. Similarly, diverse human progeroid syndromes are caused by mutations in ZMPSTE24 or LMNA genes. To elucidate the molecular mechanisms underlying these devastating diseases, we have analysed the transcriptional alterations occurring in tissues from Zmpste24-deficient mice. We demonstrate that Zmpste24 deficiency elicits a stress signalling pathway that is evidenced by a marked upregulation of p53 target genes, and accompanied by a senescence phenotype at the cellular level and accelerated ageing at the organismal level. These phenotypes are largely rescued in Zmpste24-/-Lmna+/- mice and partially reversed in Zmpste24-/-p53-/- mice. These findings provide evidence for the existence of a checkpoint response activated by the nuclear abnormalities caused by prelamin A accumulation, and support the concept that hyperactivation of the tumour suppressor p53 may cause accelerated ageing.

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

“…Previous studies had shown that lamin A/C depletion is a trigger of p21 expression (Moiseeva, Bourdeau, Vernier, Dabauvalle, & Ferbeyre, 2011). Moreover, accumulation of toxic levels of prelamin A or progerin, the mutated prelamin A form found in HGPS, was associated with upregulation of p53 target genes, including CDKN1A (Kudlow, Stanfel, Burtner, Johnston, & Kennedy, 2008; Varela et al, 2005). However, the molecular link between lamin A/C and p21 modulation remained elusive.…”

Mice with reduced expression of the telomere‐associated protein Ft1 develop p53‐sensitive progeroid traits

“…The cellular defects found in progeroid diseases that also characterize normal human aging include DNA damage and genome instability, telomere attrition, epigenetic alterations of histones, aberrations in the nuclear lamina, and cell senescence (de Boer et al, 2002; Liu et al., 2005; Osorio, Ugalde, et al., 2011; Varela et al., 2005). …”

“…Consistent with these findings, in Ft1 kof/kof mutant mice, mutations in p53 rescue the body weight and sterility phenotypes but do not improve survival. Impairment of the p53 function also ameliorates the progeroid phenotypes in BRCA1‐deficient mice (Cao, Li, Kim, Brodie & Deng, 2003) and in HGPS mouse models (Varela et al., 2005). However, p53 deficiency worsens the progeroid phenotype in telomere dysfunctional mice (Begus‐Nahrmann et al., 2009).…”

“…Also, in this case, a mouse model replicates the progeroid phenotype of the disease (Osorio, Ugalde, et al., 2011). A partial recovery of the ZMPSTE24 −/− phenotype is obtained by depletion of the tumor suppressor protein p53, pointing to a role of DNA damage in the pathophysiology of this progeria (Varela et al., 2005). …”

Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice

“…Recent work suggests senescent cell burden can be dramatically increased by chronological aging or in models of progeria (Lecka‐Czernik et al ., 1997; Baker et al ., 2004; Varela et al ., 2005), high‐fat feeding (Shi et al ., 2007), diabetes (Verzola et al ., 2008), tobacco exposure (Nyunoya et al ., 2006), or atherosclerosis (Wang & Bennett, 2012), and short‐term treatment with ‘senolytic’ drugs in chronologically aged or progeroid mice alleviates several aging‐related phenotypes (Zhu et al ., 2015a,b). However, effects of long‐term senescent cell clearance on vascular reactivity and structure with aging or chronic hypercholesterolemia remain unknown.…”