Accumulation of prelamin A induces premature aging through mTOR overactivation

Abstract

Hutchinson‐Gilford progeria syndrome (HGPS) arises when a truncated form of farnesylated prelamin A accumulates at the nuclear envelope, leading to misshapen nuclei. Previous studies of adult Zmpste24‐deficient mice, a mouse model of progeria, have reported a metabolic response involving inhibition of the mTOR (mammalian target of rapamycin) kinase and activation of autophagy. However, exactly how mTOR or autophagy is involved in progeria remains unclear. Here, we investigate this question by crossing Zmpste24+/− mice with mice hypomorphic in mTOR (mTOR△/+), or mice heterozygous in autophagy‐related gene 7 (Atg7+/−). We find that accumulation of prelamin A induces premature aging through mTOR overactivation and impaired autophagy in newborn Zmpste24−/− mice. Zmpste24−/− mice with genetically reduced mTOR activity, but not heterozygosity in Atg7, show extended lifespan. Moreover, mTOR inhibition partially restores autophagy and S6K1 activity. We also show that progerin interacts with the Akt phosphatase to promote full activation of the Akt/mTOR signaling pathway. Finally, although we find that genetic reduction of mTOR postpones premature aging in Zmpste24 KO mice, frequent embryonic lethality occurs. Together, our findings show that over‐activated mTOR contributes to premature aging in Zmpste24−/− mice, and suggest a potential strategy in treating HGPS patients with mTOR inhibitors.

Cell immortalization facilitates prelamin A clearance by increasing both cell proliferation and autophagic flux

“…In addition, it is in the immortalized Zmpste24 KO cells where we do not observe an accumulation of prelamin A, just the contrary that occurs in the primary cells. All of these data fit perfectly with results published very recently, indicating that accumulation of prelamin A facilitates the appearance of premature aging, through the hyperactivation of mTORC1 [24].…”

“…However, and probably as a consequence of the immortalization process, immortalized Zmpste24 KO cells presented a basal decrease in p27 protein levels associated with an almost undetectable level of prelamin A protein, probably by an improved replication capacity of these cells and related with a higher autophagic flux. In addition, immortalized Zmpste24 KO cells presented a decrease in mTORC1 signaling pathway, probably by a reduction in the toxicity of prelamin A accumulation, as it has been recently proposed [ 24 ].…”

Genetic reduction of mTOR extends lifespan in a mouse model of Hutchinson‐Gilford Progeria syndrome

“…In contrast to cells from embryos and newborn mice, however, signaling downstream of mTOR was found to be inhibited in LMNA G/G adult tissues, particularly in the heart. These findings suggest that hyperactivation of mTOR signaling may be an early event in the onset of HGPS pathology in Mtor +/+ LMNA G/G mice, but its activity is age‐, phenotype‐, and tissue‐dependent, similar to what has been observed for Zmpste24 −/− mice (Pan et al, 2020 ), and which may be informative to the rational design of a therapeutic approach involving chemical inhibition of mTOR signaling.…”

“…Analysis of mTOR signaling in fibroblasts derived from newborn mice demonstrated that increased activation of the downstream effector S6 protein kinase (S6K) in Mtor +/+ LMNA G/G was normalized in Mtor Δ/+ LMNA G/G , consistent with lifespan extension observed in S6K‐null mice (Selman et al, 2009 ). Genetic reduction of Mtor has previously been reported to normalize increased mTOR/S6K1 activity, partially restore autophagy and postpone the premature aging phenotype in Zmpste24 ‐null mice (Pan et al, 2020 ). Hyperactivation of S6K has also been observed in adipocyte precursor and osteosarcoma cell lines expressing LMNA mutations associated with Type 2 Familial Partial Lipodystrophy (FPLD2) and Mandibuloacral Dysplasia (MADA), respectively (Evangelisti et al, 2015 ; Pellegrini et al, 2019 ).…”

Molecular and Mechanobiological Pathways Related to the Physiopathology of FPLD2

“…Therefore, other molecular pathways affecting adipocytic and vascular differentiation and activity should be investigated. Among these pathways, altered autophagic degradation appears to be a common molecular mechanism for laminopathies that should be scrutinized in more detail [14,[65][66][67][68][69]. This process, which involves the mTOR pathway, will be described in detail hereafter.…”