Progeroid syndrome patients with ZMPSTE24 deficiency could benefit when treated with rapamycin and dimethylsulfoxide

Abstract

Patients with progeroid syndromes such as mandibuloacral dysplasia, type B (MADB) and restrictive dermopathy (RD) harbor mutations in zinc metalloproteinase (ZMPSTE24), an enzyme essential for posttranslational proteolysis of prelamin A to form mature lamin A. Dermal fibroblasts from these patients show increased nuclear dysmorphology and reduced proliferation; however, the efficacy of various pharmacological agents in reversing these cellular phenotypes remains unknown. In this study, fibroblasts from MADB patients exhibited marked nuclear abnormalities and reduced proliferation that improved upon treatment with rapamycin and dimethylsulfoxide but not with other agents, including farnesyl transferase inhibitors. Surprisingly, fibroblasts from an RD patient with a homozygous null mutation in ZMPSTE24, resulting in exclusive accumulation of prelamin A with no lamin A on immunoblotting of cellular lysate, exhibited few nuclear abnormalities and near-normal cellular proliferation. An unbiased proteomic analysis of the cellular lysate from RD fibroblasts revealed a lack of processing of vimentin, a cytoskeletal protein. Interestingly, the assembly of the vimentin microfibrils in MADB fibroblasts improved with rapamycin and dimethylsulfoxide. We conclude that rapamycin and dimethylsulfoxide are beneficial for improving nuclear morphology and cell proliferation of MADB fibroblasts. Data from a single RD patient's fibroblasts also suggest that prelamin A accumulation by itself might not be detrimental and requires additional alterations at the cellular level to manifest the phenotype.

The Cutting Edge: The Role of mTOR Signaling in Laminopathies

“…Rapamycin treatment may be a therapeutic strategy for MADB as well. Indeed, it has been demonstrated that inhibition of the mTOR signaling pathway induces improvement of nuclear aberrations and ameliorates the overall phenotype of fibroblasts from MADB patients, even if changes in the phosphorylation status of mTOR have not been determined ( Figure 4 ) [ 171 ].…”

Restrictive dermopathy due to ZMPSTE24 deficiency

“…Additionally, fibroblasts of a patient with ZMPSTE24 deficiency have been recently reported to exhibit improved nuclear morphology and cell proliferation after treatment with rapamycin and dimethylsulfoxide. This observation may open a novel therapeutic avenue for restrictive dermopathy in the future (Akinci et al , 2017).…”

The Implication of Low Dose Dimethyl Sulfoxide on Mitochondrial Function and Oxidative Damage in Cultured Cardiac and Cancer Cells

“…Previously, a dose of 0.1% DMSO was shown to induce epigenetic modifications, which impaired the expression of genes involved in cellular senescence and DNA repair in a 3D maturing cardiac model [ 3 ]. In contrast, 1% DMSO exposure significantly improved the nuclear morphology and antioxidant status of dermal fibroblasts [ 8 ]. This improvement was determined to be even higher than that observed in known antioxidants, such as N-acetylcysteine [ 8 ] Similarly, in colon cancer cells, low DMSO doses (0.1–1.5%) were shown to reduce the cellular levels of reactive oxygen species (ROS) and the cells proliferative activity relative to the control [ 9 ].…”

“…In contrast, 1% DMSO exposure significantly improved the nuclear morphology and antioxidant status of dermal fibroblasts [ 8 ]. This improvement was determined to be even higher than that observed in known antioxidants, such as N-acetylcysteine [ 8 ] Similarly, in colon cancer cells, low DMSO doses (0.1–1.5%) were shown to reduce the cellular levels of reactive oxygen species (ROS) and the cells proliferative activity relative to the control [ 9 ]. Literature has further shown that the addition of DMSO (1%) to culture medium at the formation stage of cardiomyocyte progenitor cells stimulates the differentiation of pluripotent stem cells (PSCs) into cardiomyocytes by a 1.5-fold increase [ 10 ].…”