Abstract
Ataxia telangiectasia (AT) is a rare genetic neurodegenerative disease. To date, there is no available cure for the illness, but the use of glucocorticoids has been shown to alleviate the neurological symptoms associated with AT. While studying the effects of dexamethasone (dex) in AT fibroblasts, by chance we observed that the nucleoplasmic Lamin A/C was affected by the drug. In addition to the structural roles of A-type lamins, Lamin A/C has been shown to play a role in the regulation of gene expression and cell cycle progression, and alterations in the LMNA gene is cause of human diseases called laminopathies. Dex was found to improve the nucleoplasmic accumulation of soluble Lamin A/C and was capable of managing the large chromatin Lamin A/C scaffolds contained complex, thus regulating epigenetics in treated cells. In addition, dex modified the interactions of Lamin A/C with its direct partners lamin associated polypeptide (LAP) 2a, Retinoblastoma 1 (pRB) and E2F Transcription Factor 1 (E2F1), regulating local gene expression dependent on E2F1. These effects were differentially observed in both AT and wild type (WT) cells. To our knowledge, this is the first reported evidence of the role of dex in Lamin A/C dynamics in AT cells, and may represent a new area of research regarding the effects of glucocorticoids on AT. Moreover, future investigations could also be extended to healthy subjects or to other pathologies such as laminopathies since glucocorticoids may have other important effects in these contexts as well.
Highlights
Ataxia Telangiectasia (AT) is a rare autosomal recessive disease caused by the ataxia telangiectasia mutated (ATM) gene[1,2,3] encoding for the ATM protein, a large serine/threonine kinase belonging to the PI3 kinase-like kinase (PIKK) family[4]
The documented phenotype was tested on derived hTERT immortalized fibroblasts wild type (WT) hT and Ataxia telangiectasia (AT) 648 hT and by using this cellular model, we were able to further confirm the dex dependent nuclear accumulation of Lamin A/C
In order to define the extend of soluble lamin levels of the total nucleoplasmic lamin amount, a solubilization assay was performed as described by Kolb et al.[29]
Summary
Ataxia Telangiectasia (AT) is a rare autosomal recessive disease caused by the ataxia telangiectasia mutated (ATM) gene[1,2,3] encoding for the ATM protein, a large serine/threonine kinase belonging to the PI3 kinase-like kinase (PIKK) family[4]. A-type lamins are encoded by the LMNA gene and are the main constituents of nuclear lamina, acting as a shell to regulate nuclear shape f unctions[22,23] In addition to their purely mechanical function involving their interaction with other nuclear periphery c omponents[24,25], in the last few years a growing body of evidence has revealed another role of nucleoplasmic lamin. Mutations in the LMNA gene cause several human diseases called laminopathies[38], and one of the most severe of the laminopathies is the premature aging disease called Hutchinson-Gilford progeria syndrome (HGPS) This pathology shows several cellular defects such as impaired cell signaling and cell cycle regulation, compromised DNA repair and premature senescence[39,40]. We were able to show that dex can alter Lamin dynamics and signaling, opening a challenging new area of investigation concerning cell biochemistry and the specific role that dex can play in the AT pathology
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