Abstract
Down syndrome (DS) is a developmental disorder that results from the trisomy of chromosome 21. DS patients show several abnormalities including cognitive deficits. Here, we show enhanced activation of the extracellular signal-regulated kinase (ERK), a kinase that critically regulates synaptic plasticity and memory, in a hippocampal cell line derived from trisomy 16 mouse foetus. In addition, these cells show enhanced activation of p38 mitogen-activated protein kinase (p38 MAPK). The hyper-activation of ERK and p38 MAPK is significantly reduced by a small peptide, Gly-Pro-Glu (GPE), derived from insulin-like growth factor-1. In addition, the trisomic cells show reduced level of inhibitory phosphorylation of glycogen synthase kinase-3β (GSK-3β), which is enhanced by GPE. Furthermore, the trisomic cells do not show ERK activation in response to KCl depolarization or forskolin treatment. Importantly, ERK activation by these stimuli is observed after GPE treatment of the cells. These results suggest that GPE may help reduce aberrant signalling in the trisomic neurons by affecting MAPK and GSK-3β activation.
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Acknowledgements
The H1b and the HTk cells were used under agreement with University of South Florida Board of Trustees on behalf of the University of Chile (USF/UC). TA and SKS thank DIC section of National Brain Research Centre for computer support.
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This study was funded by Core grant to the National Brain Research Centre from Department of Biotechnology, India. Dr. Pablo Caviedes is a recipient of grants from Fondecyt (Chile), grants # 1130241, 1161450. Dr. Pablo Caviedes also acknowledges support from CONICYT for funding of Basal Centre, CeBiB, FB0001 and P09-022-F from ICM-ECONOMIA, Chile.
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Conceptualization, Tushar Arora and Shiv Kumar Sharma; formal analysis, Tushar Arora; investigation, Tushar Arora; methodology, Tushar Arora; resources, Pablo Caviedes and Shiv Kumar Sharma; supervision, Shiv Kumar Sharma; visualisation, Tushar Arora; writing—original draft, Tushar Arora; writing—review and editing, Tushar Arora, Pablo Caviedes and Shiv Kumar Sharma. Pablo Caviedes developed the cell lines that have been used in the experiments described herein.
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TA and SKS declare no conflict of interests. PC declares patent protection on the H1b and HTk cell lines.
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Arora, T., Caviedes, P. & Sharma, S.K. Effects of a Tripeptide on Mitogen-Activated Protein Kinase and Glycogen Synthase Kinase Activation in a Cell Line Derived from the Foetal Hippocampus of a Trisomy 16 Mouse: an Animal Model of Down Syndrome . Neurotox Res 37, 714–723 (2020). https://doi.org/10.1007/s12640-019-00130-x
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DOI: https://doi.org/10.1007/s12640-019-00130-x