Spatiotemporal analysis of Rest expression in the brain of Ts1Cje mouse model of Down syndrome

Chong, Teik Lim (2022) Spatiotemporal analysis of Rest expression in the brain of Ts1Cje mouse model of Down syndrome. [Project Paper] (Submitted)

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Abstract

Down syndrome (DS) is a developmental genetic defect caused by aneuploidy of full/partial trisomy of human chromosome 21 (HSA21). It is characterised by complex clinical features, including significant neuropathology deficits in the central nervous system (CNS). Repressor element-1 silencing transcription factor (REST) is an epigenetic transcription repressor for neuronal gene regulation. Previous studies proposed the perturbed Rest expression in DS mouse models against wildtype. However, the results across the studies are inconsistent; each study only covered a part of the neurodevelopmental stages. Moreover, REST nuclear translocation is essential to exert repression on target genes. To date, the failure of REST nuclear translocation has been implicated in other neurodegenerative diseases but not DS. Therefore, a comprehensive spatiotemporal analysis of Rest expression and REST nuclear localisation studies were performed to determine the relationship between REST and DS. Objectives: To determine the spatiotemporal Rest expression and REST nuclear localisation in the brain of the Ts1Cje mouse model. Methodology: Total RNAs of Ts1Cje and wildtype neurospheres and embryonic and postnatal brains were reverse-transcribed into cDNAs and analysed with quantitative-polymerase chain reaction (qPCR) to determine the spatiotemporal profile of Rest expression. REST protein expression was analysed with Western blot. Immunohistochemistry was performed to characterise the subcellular localisation of REST. Results: Spatiotemporal analysis shows a significantly downregulated Rest expression in Ts1Cje against the wildtype model at the more homogeneous neural progenitor stage (neurospheres). Embryonic & postnatal stages and REST protein analysis all show insignificant REST expression differences between both models. Nuclear localisation analysis shows a remarkably different REST subcellular localised pattern between both models. Discussion: The downregulated Rest expression in the early neurodevelopment stage dysregulates the neuronal gene expression causing premature neurodifferentiation and neural stem cell pool depletion. The loss of nuclear REST function for epigenetic repression activity causes deficits in neuroprotection and functional stress resilience. Conclusion: The comprehensive Rest expression profiling and REST protein subcellular localisation analysis implicated both downregulated Rest expression and failed REST nuclear translocation attributed to the DS neuropathology.

Item Type:	Project Paper
Faculty:	Faculty of Medicine and Health Science
Depositing User:	Ms. Nor Safa'aton Saidin
Date Deposited:	22 Aug 2023 04:40
Last Modified:	22 Aug 2023 04:40
URI:	http://psaspb.upm.edu.my/id/eprint/1357

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