MyMedR

Displaying all 4 publications

Abstract:

Sort:

Fulltext Phenotype microarrays reveal metabolic dysregulations of neurospheres derived from embryonic Ts1Cje mouse model of Down syndrome

Seth EA, Lee HC, Yusof HHBM, Nordin N, Cheah YK, Ho ETW, et al.

PLoS One, 2020;15(7):e0236826.
PMID: 32730314 DOI: 10.1371/journal.pone.0236826

Down syndrome (DS), is the most common cause of intellectual disability, and is characterized by defective neurogenesis during perinatal development. To identify metabolic aberrations in early neurogenesis, we profiled neurospheres derived from the embryonic brain of Ts1Cje, a mouse model of Down syndrome. High-throughput phenotypic microarray revealed a significant decrease in utilisation of 17 out of 367 substrates and significantly higher utilisation of 6 substrates in the Ts1Cje neurospheres compared to controls. Specifically, Ts1Cje neurospheres were less efficient in the utilisation of glucose-6-phosphate suggesting a dysregulation in the energy-producing pathway. T Cje neurospheres were significantly smaller in diameter than the controls. Subsequent preliminary study on supplementation with 6-phosphogluconic acid, an intermediate of glucose-6-phosphate metabolism, was able to rescue the Ts1Cje neurosphere size. This study confirmed the perturbed pentose phosphate pathway, contributing to defects observed in Ts1Cje neurospheres. We show for the first time that this comprehensive energetic assay platform facilitates the metabolic characterisation of Ts1Cje cells and confirmed their distinguishable metabolic profiles compared to the controls.

Matched MeSH terms: Down Syndrome/metabolism
Fulltext Expression Profiling of Notch Signalling Pathway and Gamma-Secretase Activity in the Brain of Ts1Cje Mouse Model of Down Syndrome

Yusof HH, Lee HC, Seth EA, Wu X, Hewitt CA, Scott HS, et al.

J Mol Neurosci, 2019 Apr;67(4):632-642.
PMID: 30758748 DOI: 10.1007/s12031-019-01275-2

Notch signalling pathway is involved in the proliferation of neural progenitor cells (NPCs), to inhibit neuronal cell commitment and to promote glial cell fate. Notch protein is cleaved by gamma-secretase, a multisubunit transmembrane protein complex that releases the Notch intracellular domain (NICD) and subsequently activates the downstream targets. Down syndrome (DS) individuals exhibit an increased number of glial cells (particularly astrocytes), and reduced number of neurons suggesting the involvement of Notch signalling pathway in the neurogenic-to-gliogenic shift in DS brain. Ts1Cje is a DS mouse model that exhibit similar neuropathology to human DS individuals. To date, the spatiotemporal gene expression of the Notch and gamma-secretase genes have not been characterised in Ts1Cje mouse brain. Understanding the expression pattern of Notch and gamma-secretase genes may provide a better understanding of the underlying mechanism that leads to the shift. Gene expression analysis using RT-qPCR was performed on early embryonic and postnatal development of DS brain. In the developing mouse brain, mRNA expression analysis showed that gamma-secretase members (Psen1, Pen-2, Aph-1b, and Ncstn) were not differentially expressed. Notch2 was found to be downregulated in the developing Ts1Cje brain samples. Postnatal gene expression study showed complex expression patterns and Notch1 and Notch2 genes were found to be significantly downregulated in the hippocampus at postnatal day 30. Results from RT-qPCR analysis from E15.5 neurosphere culture showed an increase of expression of Psen1, and Aph-1b but downregulation of Pen-2 and Ncstn genes. Gamma-secretase activity in Ts1Cje E15.5 neurospheres was significantly increased by fivefold. In summary, the association and the role of Notch and gamma-secretase gene expression throughout development with neurogenic-to-gliogenic shift in Ts1Cje remain undefined and warrant further validation.

Matched MeSH terms: Down Syndrome/metabolism*
Gene and protein expression profiles of JAK-STAT signalling pathway in the developing brain of the Ts1Cje down syndrome mouse model

Lee HC, Md Yusof HH, Leong MP, Zainal Abidin S, Seth EA, Hewitt CA, et al.

Int J Neurosci, 2019 Sep;129(9):871-881.
PMID: 30775947 DOI: 10.1080/00207454.2019.1580280

Aims: The JAK-STAT signalling pathway is one of the key regulators of pro-gliogenesis process during brain development. Down syndrome (DS) individuals, as well as DS mouse models, exhibit an increased number of astrocytes, suggesting an imbalance of neurogenic-to-gliogenic shift attributed to dysregulated JAK-STAT signalling pathway. The gene and protein expression profiles of JAK-STAT pathway members have not been characterised in the DS models. Therefore, we aimed to profile the expression of Jak1, Jak2, Stat1, Stat3 and Stat6 at different stages of brain development in the Ts1Cje mouse model of DS. Methods: Whole brain samples from Ts1Cje and wild-type mice at embryonic day (E)10.5, E15, postnatal day (P)1.5; and embryonic cortex-derived neurospheres were collected for gene and protein expression analysis. Gene expression profiles of three brain regions (cerebral cortex, cerebellum and hippocampus) from Ts1Cje and wild-type mice across four time-points (P1.5, P15, P30 and P84) were also analysed. Results: In the developing mouse brain, none of the Jak/Stat genes were differentially expressed in the Ts1Cje model compared to wild-type mice. However, Western blot analyses indicated that phosphorylated (p)-Jak2, p-Stat3 and p-Stat6 were downregulated in the Ts1Cje model. During the postnatal brain development, Jak/Stat genes showed complex expression patterns, as most of the members were downregulated at different selected time-points. Notably, embryonic cortex-derived neurospheres from Ts1Cje mouse brain expressed lower Stat3 and Stat6 protein compared to the wild-type group. Conclusion: The comprehensive expression profiling of Jak/Stat candidates provides insights on the potential role of the JAK-STAT signalling pathway during abnormal development of the Ts1Cje mouse brains.

Matched MeSH terms: Down Syndrome/metabolism
Fulltext Defects in nerve conduction velocity and different muscle fibre-type specificity contribute to muscle weakness in Ts1Cje Down syndrome mouse model

Bala U, Leong MP, Lim CL, Shahar HK, Othman F, Lai MI, et al.

PLoS One, 2018;13(5):e0197711.
PMID: 29795634 DOI: 10.1371/journal.pone.0197711

BACKGROUND: Down syndrome (DS) is a genetic disorder caused by presence of extra copy of human chromosome 21. It is characterised by several clinical phenotypes. Motor dysfunction due to hypotonia is commonly seen in individuals with DS and its etiology is yet unknown. Ts1Cje, which has a partial trisomy (Mmu16) homologous to Hsa21, is well reported to exhibit various typical neuropathological features seen in individuals with DS. This study investigated the role of skeletal muscles and peripheral nerve defects in contributing to muscle weakness in Ts1Cje mice.
RESULTS: Assessment of the motor performance showed that, the forelimb grip strength was significantly (P<0.0001) greater in the WT mice compared to Ts1Cje mice regardless of gender. The average survival time of the WT mice during the hanging wire test was significantly (P<0.0001) greater compared to the Ts1Cje mice. Also, the WT mice performed significantly (P<0.05) better than the Ts1Cje mice in the latency to maintain a coordinated motor movement against the rotating rod. Adult Ts1Cje mice exhibited significantly (P<0.001) lower nerve conduction velocity compared with their aged matched WT mice. Further analysis showed a significantly (P<0.001) higher population of type I fibres in WT compared to Ts1Cje mice. Also, there was significantly (P<0.01) higher population of COX deficient fibres in Ts1Cje mice. Expression of Myf5 was significantly (P<0.05) reduced in triceps of Ts1Cje mice while MyoD expression was significantly (P<0.05) increased in quadriceps of Ts1Cje mice.
CONCLUSION: Ts1Cje mice exhibited weaker muscle strength. The lower population of the type I fibres and higher population of COX deficient fibres in Ts1Cje mice may contribute to the muscle weakness seen in this mouse model for DS.

Matched MeSH terms: Down Syndrome/metabolism