Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic condition associated with mutations in the LMNA gene. This disease recapitulates some aspects of normal aging, such as hair loss, thin skin, joint stiffness, and atherosclerosis. The latter leads to heart attack or stroke that causes death at an average age of 14.6 years in children with HGPS. The typical LMNA mutation results in the production of a truncated prelamin A protein, progerin, that remains permanently farnesylated and abnormally associated with the nuclear envelope. Farnesyltransferase inhibitors (FTIs) reverse nuclear structure abnormalities that are characteristic of HGPS cells. The first clinical trial using the FTI, Ionafarnib, demonstrated some improvements in HGPS children and, in particular, showed a decrease in arterial stiffness. Recently, we reported that sulforaphane, an antioxidant derived from cruciferous vegetables, efficiently stimulates autophagy and enhances progerin clearance in HGPS fibroblasts. In the present study, we investigated the effect of combined lonafarnib and sulforaphane treartment in HGPS fibroblast cultures. We report that co-administration of both drugs exerts a synergistic and additive positive effect on autophagy activity but was cytotoxic to HGPS cells. In contrast, intermittent treatment with lonafarnib followed by sulforaphane separately and in repeated cycles rescued the HGPS cellular phenotype. We propose that intermittent treatment with FTI and SFN separately might be a promising therapeutic avenue for children with HGPS.
Highlights
Hutchinson-Gilford progeria syndrome is a premature aging disorder linked to mutations in the lamin A gene [1, 2]
We found that decreasing the Farnesyltransferase inhibitors (FTIs) concentration to 0.06 μM slightly increased the growth rate of Hutchinson-Gilford progeria syndrome (HGPS) cells (p = 0.689; Figure 1A)
When the cells were treated with both FTI and SFN at concentrations of 0.25 μM for a period of 3 days, the growth rates were significantly reduced in both control (p = 0.029) and HGPS cells (p = 0.030), which indicates that this combination was toxic (Figure 1A)
Summary
Hutchinson-Gilford progeria syndrome is a premature aging disorder linked to mutations in the lamin A gene [1, 2]. Due to the point mutation G608G, the cleavage site for ZMPSTE24 is missing, leading to the production of a permanently farnesylated protein that remains tightly anchored to the nuclear envelope [6]. HGPS cells treated with FTIs exhibited successful delocalization of progerin from the nuclear envelope to the nucleoplasm [5] With this outcome, the efficacy of FTIs treatment in progeria mouse models was tested. Three FTI studies using progeria mouse models have shown substantial improvements in body weight, life span, and adipose tissue [5]. Under these treatment conditions, nonfarnesylated prelamin A and nonfarnesylated progerin still accumulate and remain in the nucleus. The positive effects of FTI in mouse models of HGPS strongly supported the use of Ionafarnib in the first clinical trial, which showed improvements in body weight, bone rigidity and mineral density as well as a reduction in arterial stiffness in children with HGPS [5, 19]
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