Date Published: April 2, 2018
Publisher: Public Library of Science
Author(s): Michele Menotta, Sara Orazi, Anna Maria Gioacchini, Chiara Spapperi, Anastasia Ricci, Luciana Chessa, Mauro Magnani, Robert S. Weiss.
Ataxia telangiectasia (A-T) is an incurable and rare hereditary syndrome. In recent times, treatment with glucocorticoid analogues has been shown to improve the neurological symptoms that characterize this condition, but the molecular mechanism of action of these analogues remains unknown. Hence, the aim of this study was to gain insight into the molecular mechanism of action of glucocorticoid analogues in the treatment of A-T by investigating the role of Dexamethasone (Dexa) in A-T lymphoblastoid cell lines. We used 2DE and tandem MS to identify proteins that were influenced by the drug in A-T cells but not in healthy cells. Thirty-four proteins were defined out of a total of 746±63. Transcriptome analysis was performed by microarray and showed the differential expression of 599 A-T and 362 wild type (WT) genes and a healthy un-matching between protein abundance and the corresponding gene expression variation. The proteomic and transcriptomic profiles allowed the network pathway analysis to pinpoint the biological and molecular functions affected by Dexamethasone in Dexa-treated cells. The present integrated study provides evidence of the molecular mechanism of action of Dexamethasone in an A-T cellular model but also the broader effects of the drug in other tested cell lines.
Ataxia Telangiectasia (A-T) is a rare genetic syndrome caused by mutations in the ataxia telangiectasia mutated (ATM)  gene. The gene product codes for a protein kinase belonging to the PI3 Kinase-like Kinase (PIKK) . Depending on the level of the mutation, the resultant loss of ATM protein expression or function can lead to pleiotropic clinical phenotypes  such as ataxia, oculocutaneous teleangiectasias, immunodeficiency, infections, radio sensitivity and proneness to cancer and neurodegenerative disorders. Typically, A-T patients are wheel-chair dependent by the age of ten, and their life expectancy is around twenty-five years. The ATM gene ensures DNA repair in the nucleus , while its role in the cytosol is still poorly understood [5–7].
Results illustrated in the present study represent the first integrated analysis by proteomic and transcriptomic, to investigate in vitro the Dexamethasone molecular mechanism of action in an A-T established model, as this drug is employed as effective therapy in A-T patients [11,12,16,18]. The chosen spots selection approach allowed highlighting the protein amounts variation in A-T cells in response to Dexa treatment, rather than the generalised cellular glucocorticoid response that, in our opinion, represent an attractive basis to comprehend the particular outcome of glucocorticoid usage in ataxia telangiectasia treatment. Some of the selected proteins in AT129RM showed also a basal dissimilar expression pattern compared to untreated WT (depending on A-T status?) but all of them showed a differential treatment response behaviour than WT. In fact, we were not able to observe any simple protein recovery in treated A-T.