Cell cycle and cell size regulation in Down Syndrome cells

Rosner, Margit; Kowalska, Agata; Freilinger, Angelika; Ar, Prusa; Márton, Erika; Hengstschläger, Markus

doi:10.1007/978-3-7091-6721-2_4

Cited by 7 publications

(5 citation statements)

References 13 publications

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“…The differential transcriptome map analyzed show the under‐expression of the genes encoding for the mitochondrial forms of the enzymes cited ( MTFD1L and ALDH1L2 ). These data might be coherent with the hypoproliferation of trisomy 21 cells (Rosner et al, ). The balancing of their expression suggests that a compensatory mechanism linked to an important one carbon metabolism function for the viability of the cells might exist.…”

Section: Discussionsupporting

confidence: 77%

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Human trisomy 21 fibroblasts rescue methotrexate toxic effect after treatment with 5‐methyl‐tetrahydrofolate and 5‐formyl‐tetrahydrofolate

Vitale

Serpieri

Lauriola

et al. 2019

Journal Cellular Physiology

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Trisomy 21 causes Down syndrome (DS), the most common human genetic disorder and the leading genetic cause of intellectual disability. The alteration of one‐carbon metabolism was described as the possible metabolic cause of the intellectual disability development in subjects with DS. One of the biochemical pathways involved in the one‐carbon group transfer is the folate cycle. The cytotoxic drug methotrexate (MTX) is a folic acid (FA) analogue which inhibits the activity of dihydrofolate reductase enzyme involved in the one‐carbon metabolic cycle. Trisomy 21 cells are more sensitive to the MTX effect than euploid cells, and in 1986 Jérôme Lejeune and Coll. demonstrated that MTX was twice as toxic in trisomy 21 lymphocytes than in control cells. In the present work, the rescue effect on MTX toxicity mediated by FA and some of its derivatives, tetrahydrofolate (THF), 5‐formyl‐THF, and 5‐methyl‐THF, in both normal and trisomy 21 skin fibroblast cells, was evaluated. A statistically significant rescue effect was obtained by 5‐formyl‐THF, 5‐methyl‐THF, and their combination, administered together with MTX. In conclusion, trisomy 21 fibroblast cell lines showed a good response to the rescue effects of 5‐formyl‐THF and 5‐methyl‐THF on the MTX toxicity almost as normal cell lines.

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Section: Discussionsupporting

confidence: 77%

“…These data might be coherent with the hypoproliferation of trisomy 21 cells (Rosner et al, 2003). The balancing of their Table 3; gene expression ratio = 1.88; Taub & Ge, 2005).…”

Section: Discussionsupporting

confidence: 63%

Human trisomy 21 fibroblasts rescue methotrexate toxic effect after treatment with 5‐methyl‐tetrahydrofolate and 5‐formyl‐tetrahydrofolate

Vitale

Serpieri

Lauriola

et al. 2019

Journal Cellular Physiology

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“…Indeed, there is direct experimental evidence showing significant impairment of DNA repair and cell cycle in human DS cells and in animal models of DS (e.g. Contestabile et al 2007 ; Pincheira et al 1994 ; Druzhyna et al 1998 ; Maluf and Erdtmann 2001 ; Rosner et al 2003 ; Necchi et al 2015 ; Wang et al 2016 ). While various compensatory bioenergetic processes (e.g.…”

Section: Implications Conclusion and Outlookmentioning

confidence: 99%

Meta-analysis of metabolites involved in bioenergetic pathways reveals a pseudohypoxic state in Down syndrome

Pecze

Randi

Szabó

2020

Mol Med

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Clinical observations and preclinical studies both suggest that Down syndrome (DS) may be associated with significant metabolic and bioenergetic alterations. However, the relevant scientific literature has not yet been systematically reviewed. The aim of the current study was to conduct a meta-analysis of metabolites involved in bioenergetics pathways in DS to conclusively determine the difference between DS and control subjects. We discuss these findings and their potential relevance in the context of pathogenesis and experimental therapy of DS. Articles published before July 1, 2020, were identified by using the search terms “Down syndrome” and “metabolite name” or “trisomy 21” and “metabolite name”. Moreover, DS-related metabolomics studies and bioenergetics literature were also reviewed. 41 published reports and associated databases were identified, from which the descriptive information and the relevant metabolomic parameters were extracted and analyzed. Mixed effect model revealed the following changes in DS: significantly decreased ATP, CoQ10, homocysteine, serine, arginine and tyrosine; slightly decreased ADP; significantly increased uric acid, succinate, lactate and cysteine; slightly increased phosphate, pyruvate and citrate. However, the concentrations of AMP, 2,3-diphosphoglycerate, glucose, and glutamine were comparable in the DS vs. control populations. We conclude that cells of subjects with DS are in a pseudo-hypoxic state: the cellular metabolic and bio-energetic mechanisms exhibit pathophysiological alterations that resemble the cellular responses associated with hypoxia, even though the supply of the cells with oxygen is not disrupted. This fundamental alteration may be, at least in part, responsible for a variety of functional deficits associated with DS, including reduced exercise difference, impaired neurocognitive status and neurodegeneration.

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“…Taken together, our data reveal potential gene patterns which could influence the occurrence of diseases related to DS. The pathways we found dysregulated in this study are involved in cell cycle and in proliferation activity, which have been linked with neuropathologies, including Alzheimer's disease, which represents one of the typical DS comorbidities [ 67 ]. Furthermore, the expression of CD73 strongly correlates with the responses to immunity and cancer, since this protein is involved in the reinforcement of lymphocyte–endothelium interactions, inhibition of macrophage and mesenchymal cell-mediated inflammation [ 68 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome

Vaiasicca,

Melone,

James

et al. 2023

Stem Cell Res Ther

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Background Down syndrome (DS) clinical multisystem condition is generally considered the result of a genetic imbalance generated by the extra copy of chromosome 21. Recent discoveries, however, demonstrate that the molecular mechanisms activated in DS compared to euploid individuals are more complex than previously thought. Here, we utilize mesenchymal stem cells from chorionic villi (CV) to uncover the role of comprehensive functional genomics-based understanding of DS complexity. Methods Next-generation sequencing coupled with bioinformatic analysis was performed on CV obtained from women carrying fetuses with DS (DS-CV) to reveal specific genome-wide transcriptional changes compared to their euploid counterparts. Functional assays were carried out to confirm the biological processes identified as enriched in DS-CV compared to CV (i.e., cell cycle, proliferation features, immunosuppression and ROS production). Results Genes located on chromosomes other than the canonical 21 (Ch. 2, 6 and 22) are responsible for the impairment of life-essential pathways, including cell cycle regulation, innate immune response and reaction to external stimuli were found to be differentially expressed in DS-CV. Experimental validation confirmed the key role of the biological pathways regulated by those genes in the etiology of such a multisystem condition. Conclusions NGS dataset generated in this study highlights the compromised functionality in the proliferative rate and in the innate response of DS-associated clinical conditions and identifies DS-CV as suitable tools for the development of specifically tailored, personalized intervention modalities.

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Cell cycle and cell size regulation in Down Syndrome cells

Cited by 7 publications

References 13 publications

Human trisomy 21 fibroblasts rescue methotrexate toxic effect after treatment with 5‐methyl‐tetrahydrofolate and 5‐formyl‐tetrahydrofolate

Human trisomy 21 fibroblasts rescue methotrexate toxic effect after treatment with 5‐methyl‐tetrahydrofolate and 5‐formyl‐tetrahydrofolate

Meta-analysis of metabolites involved in bioenergetic pathways reveals a pseudohypoxic state in Down syndrome

Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome

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