Temsirolimus Partially Rescues the Hutchinson-Gilford Progeria Cellular Phenotype

Abstract

Hutchinson-Gilford syndrome (HGPS, OMIM 176670, a rare premature aging disorder that leads to death at an average age of 14.7 years due to myocardial infarction or stroke, is caused by mutations in the LMNA gene. Lamins help maintain the shape and stability of the nuclear envelope in addition to regulating DNA replication, DNA transcription, proliferation and differentiation. The LMNA mutation results in the deletion of 50 amino acids from the carboxy-terminal region of prelamin A, producing the truncated, farnesylated protein progerin. The accumulation of progerin in HGPS nuclei causes numerous morphological and functional changes that lead to premature cellular senescence. Attempts to reverse this HGPS phenotype have identified rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), as a drug that is able to rescue the HGPS cellular phenotype by promoting autophagy and reducing progerin accumulation. Rapamycin is an obvious candidate for the treatment of HGPS disease but is difficult to utilize clinically. To further assess rapamycin’s efficacy with regard to proteostasis, mitochondrial function and the degree of DNA damage, we tested temsirolimus, a rapamycin analog with a more favorable pharmacokinetic profile than rapamycin. We report that temsirolimus decreases progerin levels, increases proliferation, reduces misshapen nuclei, and partially ameliorates DNA damage, but does not improve proteasome activity or mitochondrial dysfunction. Our findings suggest that future therapeutic strategies should identify new drug combinations and treatment regimens that target all the dysfunctional hallmarks that characterize HGPS cells.

Machine learning for predicting lifespan-extending chemical compounds

“…Numerous studies indicate that inhibition of the TOR (Target of Rapamycin) kinase is implicated in lifespan control [ 58 , 59 ]. Temsirolimus also inhibits mTOR, and this compound has been shown to improve certain cellular phenotypes in accelerated ageing models via increasing autophagy [ 60 ].…”

Metabolic Dysfunction in Hutchinson–Gilford Progeria Syndrome

“…The basis for HGPS organismal changes lies at the cellular level. It is evident that there are anomalies in energy generation and expenditure, mostly stemming from alterations in mitochondrial function [41,42] and in signaling pathways regulating anabolic and catabolic processes in response to cues from the environment [43]. The mechanistic target of rapamycin (mTOR) protein complexes -mTORC1 and mTORC2-, regulated by AMPK and AKT kinases, sense the levels of nutrients and energy in cells and execute signals to either synthesize macromolecules when sources of energy and nutrients are high, or to activate autophagy in the context of starvation [44,45].…”

“…Some current therapies have even been noted not to affect mitochondrial dysfunction. For instance, temsirolimus, a rapamycin analog which improves many other cellular phenotypes, does not improve mitochondrial function [42]. Thus, this represents an area ripe for novel therapies for treating disease.…”

Nuclear envelopathies: a complex LINC between nuclear envelope and pathology

“…The mechanism underlying this effect seems to be an improvement of the autophagy that is found to be impaired in the heart of mutated mice. Temsirolimus was further shown to be able to partially rescue the cellular phenotype associated with HGPS [ 74 , 75 ]. MG132, a protease inhibitor, is also found to improve HGPS cellular phenotype by induction of progerin degradation by macroautophagy and splicing regulation.…”