Dokuz Eylül University Faculty of Medicine, Division of Endocrinology, İzmir, Turkey**
University of Texas Southwestern Medical Center, Division of Nutrition and Metabolic Diseases, Center for Human Nutrition, Department of Internal Medicine, Texas, USA***
University of Texas Southwestern Medical Center, Molecular and Cellular Imaging, Department of Cell Biology, Texas, USA****
Osaka University Graduate School of Medicine, Department of Pediatrics, Osaka, Japan*****
University of Texas Southwestern Medical Center, Center for Human Nutrition, Department of Internal Medicine, Division of Nutrition and Metabolic Diseases, Texas, USA
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 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 RD 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.