Decreased cyclin dependent kinase in brain of patients with Down Syndrome

doi:10.1016/0304-3940(96)12988-8

Neuroscience Letters

Volume 216, Issue 1, 20 September 1996, Pages 68-70

https://doi.org/10.1016/0304-3940(96)12988-8 Get rights and content

Abstract

In order to study whether phosphokinases might be involved in the neuropathology of Down Syndrome (DS) and Alzheimer disease (AD), cyclin dependent kinase (CDK) activity and protein, phosphokinase C (PKC) and phosphokinase A (PKA) activities have been determined in frontal lobes of DS, AD and control brains. An enzyme linked immunosorbent assay (ELISA) technique for CDK protein, and commercially available enzyme assays for CDK, PKC and PKA activities have been used. The major finding of our study was the remarkable and significant decrease of CDK protein and activity in DS brains in comparison to AD and controls. PKC and PKA were unaffected in both, AD and DS. As CDK controls cell division and differentiation, lowered CDK levels could reflect impaired proliferation and differentiation in DS.

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Cited by (22)

Neurogenesis impairment: An early developmental defect in Down syndrome
2018, Free Radical Biology and Medicine
Citation Excerpt :
There is evidence that DYRK1A increases G1 duration in a dose-dependent manner and that DYRK1A controls G1 duration by reducing cyclin D1 expression [94]. Consistent with DYRK1A overexpression in DS, cyclin D1 levels are reduced in the frontal lobe of fetuses with DS [103] and in fibroblasts of DS individuals [94]. This evidence suggests that one of the mechanisms underlying the reduced proliferation potency of the DS brain may be the DYRK1A/cyclin D1-dependent precocious exit from the cell cycle.
Down syndrome (DS) is characterized by brain hypotrophy and intellectual disability starting from early life stages. Accumulating evidence shows that the phenotypic features of the DS brain can be traced back to the fetal period since the DS brain exhibits proliferation potency reduction starting from the critical time window of fetal neurogenesis. This defect is worsened by the fact that neural progenitor cells exhibit reduced acquisition of a neuronal phenotype and an increase in the acquisition of an astrocytic phenotype. Consequently, the DS brain has fewer neurons in comparison with the typical brain. Although apoptotic cell death may be increased in DS, this does not seem to be the major cause of brain hypocellularity. Evidence obtained in brains of individuals with DS, DS-derived induced pluripotent stem cells (iPSCs), and DS mouse models has provided some insight into the mechanisms underlying the developmental defects due to the trisomic condition. Although many triplicated genes may be involved, in the light of the studies reviewed here, DYRK1A, APP, RCAN1 and OLIG1/2 appear to be particularly important determinants of many neurodevelopmental alterations that characterize DS because their triplication affects both the proliferation and fate of neural precursor cells as well as apoptotic cell death. Based on the evidence reviewed here, pathways downstream to these genes may represent strategic targets, for the design of possible interventions.
Trisomy 21 and early brain development
2012, Trends in Neurosciences
Citation Excerpt :
Specific changes have been reported for the cell cycle rate and progression in multiple organ systems, which suggests that the altered kinetics of cell production may contribute to many phenotypes. DNA synthesis and doubling times are both slower in DS fibroblasts [27,28] and DS cerebral cortex contains less cyclin-dependent kinase [29], which are indicative of lower replication rates. Recent studies have also shown that proliferation is abnormal in the developing DS forebrain [30] and cerebellum [31].
Trisomy for human chromosome 21 (Hsa21) results in Down syndrome (DS). The finished human genome sequence provides a thorough catalog of the genetic elements whose altered dosage perturbs development and function in DS. However, understanding how small alterations in the steady state transcript levels for <2% of human genes can disrupt development and function of essentially every cell presents a more complicated problem. Mouse models that recapitulate specific aspects of DS have been used to identify changes in brain morphogenesis and function. Here we provide a few examples of how trisomy for specific genes affects the development of the cortex and cerebellum to illustrate how gene dosage effects might contribute to divergence between the trisomic and euploid brains.
Elevated apoptosis in pre-mature neurons differentiated from mouse ES cells containing a single human chromosome 21
2002, Biochemical and Biophysical Research Communications
A decrease in the number and density of neurons is the most common phenotype in the brains of Down syndrome (DS) patients, causing mental retardation. Studies using primary cultured neurons from DS patients or from model mice have suggested that a defect in metabolism of reactive oxygen species, or diminished levels of glutathione, causes mitochondrial and caspase-mediated neuronal apoptosis in vitro. However, it is not well documented whether neuronal apoptosis also occurs in immature DS neurons, owing to the difficulty in isolating or identifying neuronal stem cells in human or mouse fetuses. Here we utilized an in vitro model system for neuronal differentiation, with mouse embryonic stem cells containing human chromosome 21 (TT2F/hChr.21) to examine the effect of an additional hChr.21 on the early phases of neurogenesis. The differentiation profile of TT2F/hChr.21 cells was essentially the same as those of parental TT2F ES cells. In differentiations of both TT2F and TT2F/hChr.21 cells, high level of apoptosis was observed in neuronal stem cells, but the rate of apoptosis in TT2F/hChr.21 cells was significantly higher than that of parental cells. These results suggest that quantitative changes in the level of apoptosis in DS neuronal stem cells may account for the reduction of neuronal number and density in the DS brain.
Apoptosis-associated proteins p53 and APO-1/Fas (CD95) in brains of adult patients with Down syndrome
1999, Neuroscience Letters
In Down syndrome (DS), enhanced apoptosis (programmed cell death) may play a role in the pathogenesis of characteristic mental retardation and precocious dementia of Alzheimer-type. Upregulation of p53 and APO-1/Fas (CD95) precedes apoptosis in many cell types, and a potential role for these molecules has already been demonstrated in Alzheimer's disease (AD) and several other neurodegenerative diseases. We measured p53 and APO-1/Fas (CD95) protein in four different regions of cerebral cortex and cerebellum in nine adult DS patients with Alzheimer-like neuropathologic lesions compared to nine controls. Quantitative ELISA demonstrated higher frontal lobe (mean±SD: 0.10±0.035 vs. 0.041±0.016 ng/mg protein), temporal lobe (0.062±0.021 vs. 0.032±0.019 ng/mg protein) and cerebellar levels (0.078±0.030 vs. 0.039±0.032 ng/mg protein) of p53 protein, and higher temporal lobe (mean±SD: 12.3±4.3 vs. 5.3±2.0 U/mg protein) and cerebellar levels (5.9±1.4 vs. 2.9±1.1 U/mg protein) of APO-1/Fas (CD95) protein. The results suggest that p53- or APO-1/Fas (CD95)-associated apoptosis may be an important feature of neurodegeneration in DS.
A cluster of protein kinases and phosphatases modulated in fetal Down syndrome (trisomy 21) brain
2015, Amino Acids
Five potential reasons for the down syndrome HSCR (DS-HSCR) association: A hypothesis
2012, New Developments in Down Syndrome Research

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Decreased cyclin dependent kinase in brain of patients with Down Syndrome

Abstract

Abnormal Alzheimer like phosphorylation of tau protein by cyclin dependent kinases CDK2 and CDK5

FEBS Lett.

Action of amyloid beta protein on protein kinase C activity

Life Sci.

The cyclin dependent protein kinases and the control of cell division

FASEB J.

Synthesis of p34, the mammalian homolog of the yeast cdc2+/CDC28 protein kinase, is stimulated during adenovirus induced proliferation of primary baby rat kidney cells

Oncogene

Cdc2 family kinases phosphorylate a human cell DNA replication factor RPA and activate DNA replication

EMBO J.

Protein kinase C (PKC) level is increased in PC12 cells overexpressing transfected liver type phosphofructokinase

Biol. Cell.

Contrasting patterns of protein phosphorylation in human normal and Alzheimer brain

Exp. Neurol.

Activation at M phase of a protein kinase encoded by a starfish homologue of the cell cycle control gene cdc2

Nature

Regulation of synthesis of p34(cdc2)and its homologues and their relationship to p110(Rb) phosphorylation during cell cycle progression of normal human T cells

J. Immunol.

Evidence for the involvement of protein kinase C in neurodegenerative changes in cultured human cortical neurons

Exp. Neurol.

Synthesis of p34, the mammalian homolog of the yeast cdc2⁺/CDC28 protein kinase, is stimulated during adenovirus induced proliferation of primary baby rat kidney cells