Combinatorial Gene Effects on the Neural Progenitor Pool in Down Syndrome

Lu, Jie; Sheen, Volney L.

doi:10.5772/20888

Cited by 3 publications

(6 citation statements)

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“…This cyclical pathway may contribute to neuronal losses during neurogenesis as well as neuronal degeneration in adulthood. Several HSA21 genes have been implicated in generation of ROS including DYRK1A, DSCR1, SOD1, ETS2, S100B, APP and BACH1 [15,17]. Additionally, more recent studies would suggest a synergistic role for various HSA21 genes in induction of this pathological process.…”

Section: Genetic Mechanisms Underlying Oxidative Stress In Dsmentioning

confidence: 99%

“…Several genes on HSA21 are implicated in the abnormal neurodevelopment in DS [15]. They can affect cellular function at every stage of neural development, such as proliferation and differentiation of neuroprogenitor cells, neuronal survival and death, synapse formation, maturation and plasticity, as well as myelination.…”

Section: Genetic Mechanisms Underlying the Ds Phenotypementioning

confidence: 99%

“…Oxidative stress from over-expression of various HSA21 genes [15] could modulate DNA methylation directly through DNA damage or modification at the CpG sites, thereby preventing normal binding of DNMTs to DNA [71,72]. DNMT3L is localized on HSA21, and its triplication in DS suggests aberrant levels of expression.…”

Section: Epigenetic Mechanisms Underlying the Ds Phenotypementioning

confidence: 99%

“…Similar morphological changes have been observed in DS animal models and correlate on a molecular level with synaptic protein level changes and functionally with synaptic plasticity defects, observed through LTP, LTD and imbalance of excitatory-inhibitory neurotransmission [42][43][44][45][46][47][48][49][50]. Many genes on HSA21 (TINM1, SYNJ1, ITSN1; KCNJ6, KCNJ15, KCNE1, KCNE2; NRIP1, ETS2, PCP4, DSCR1, DYRK1A, S100B, APP, OLIG1, OLIG2) have been implicated in the synaptic pathology in DS, and the resulting phenotype likely involves a complex interrelationship between these various genes and their direct or indirect effect on various synaptic proteins [15,48]. For instance, Dyrk1A overexpression could impair synaptic vesicle endocytosis, reduce dendrite branching and spine density of neurons; these phenotypes might be attributed to Dyrk1A induced hyperphosphorylation of Tau and APP, or other synaptic proteins such as SYNJ1, resulting in impaired hippocampal-dependent learning [51][52][53].…”

Section: Genetics Mechanisms Underlying Synaptic Formation Maturatiomentioning

confidence: 99%

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Genetic and Epigenetic Mechanisms in Down Syndrome Brain

Lu¹,

Sheen²

2013

Down Syndrome

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Section: Genetic Mechanisms Underlying Oxidative Stress In Dsmentioning

confidence: 99%

Section: Genetic Mechanisms Underlying the Ds Phenotypementioning

confidence: 99%

Section: Epigenetic Mechanisms Underlying the Ds Phenotypementioning

confidence: 99%

Section: Genetics Mechanisms Underlying Synaptic Formation Maturatiomentioning

confidence: 99%

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Genetic and Epigenetic Mechanisms in Down Syndrome Brain

Lu¹,

Sheen²

2013

Down Syndrome

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“…Disturbances in cortical development lead to changes in motor, sensory, behavioral, and cognitive function in newborns, infants, children, and adolescents. DS is characterized by an array of cognitive difficulties starting early in life [ 27 ], which are attributed to deficits in cortical development including cell proliferation and migration, apoptosis, neurogenesis, synaptogenesis and gliogenesis [ 28 , 32 , 51 ], particularly in the FC. Although many of these processes have been studied during the fetal and prenatal stages of brain development in DS [ 5 , 14 , 28 , 32 , 42 , 49 , 69 , 72 , 86 ], there is a general lack of information on early postnatal brain maturation in DS.…”

Section: Discussionmentioning

confidence: 99%

Neurogenesis and neuronal differentiation in the postnatal frontal cortex in Down syndrome

Utagawa

Moreno

Schafernak

et al. 2022

acta neuropathol commun

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Although Down syndrome (DS), the most common developmental genetic cause of intellectual disability, displays proliferation and migration deficits in the prenatal frontal cortex (FC), a knowledge gap exists on the effects of trisomy 21 upon postnatal cortical development. Here, we examined cortical neurogenesis and differentiation in the FC supragranular (SG, II/III) and infragranular (IG, V/VI) layers applying antibodies to doublecortin (DCX), non-phosphorylated heavy-molecular neurofilament protein (NHF, SMI-32), calbindin D-28K (Calb), calretinin (Calr), and parvalbumin (Parv), as well as β-amyloid (APP/Aβ and Aβ1–42) and phospho-tau (CP13 and PHF-1) in autopsy tissue from age-matched DS and neurotypical (NTD) subjects ranging from 28-weeks (wk)-gestation to 3 years of age. Thionin, which stains Nissl substance, revealed disorganized cortical cellular lamination including a delayed appearance of pyramidal cells until 44 wk of age in DS compared to 28 wk in NTD. SG and IG DCX-immunoreactive (-ir) cells were only visualized in the youngest cases until 83 wk in NTD and 57 wk DS. Strong SMI-32 immunoreactivity was observed in layers III and V pyramidal cells in the oldest NTD and DS cases with few appearing as early as 28 wk of age in layer V in NTD. Small Calb-ir interneurons were seen in younger NTD and DS cases compared to Calb-ir pyramidal cells in older subjects. Overall, a greater number of Calb-ir cells were detected in NTD, however, the number of Calr-ir cells were comparable between groups. Diffuse APP/Aβ immunoreactivity was found at all ages in both groups. Few young cases from both groups presented non-neuronal granular CP13 immunoreactivity in layer I. Stronger correlations between brain weight, age, thionin, DCX, and SMI-32 counts were found in NTD. These findings suggest that trisomy 21 affects postnatal FC lamination, neuronal migration/neurogenesis and differentiation of projection neurons and interneurons that likely contribute to cognitive impairment in DS.

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Perspectives on pain in Down syndrome

Shaikh

2023

Medicinal Research Reviews

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Down syndrome (DS) or trisomy 21 is a genetic condition often accompanied by chronic pain caused by congenital abnormalities and/or conditions, such as osteoarthritis, recurrent infections, and leukemia. Although DS patients are more susceptible to chronic pain as compared to the general population, the pain experience in these individuals may vary, attributed to the heterogenous structural and functional differences in the central nervous system, which might result in abnormal pain sensory information transduction, transmission, modulation, and perception. We tried to elaborate on some key questions and possible explanations in this review. Further clarification of the mechanisms underlying such abnormal conditions induced by the structural and functional differences is needed to help pain management in DS patients.

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Combinatorial Gene Effects on the Neural Progenitor Pool in Down Syndrome

Cited by 3 publications

References 189 publications

Genetic and Epigenetic Mechanisms in Down Syndrome Brain

Genetic and Epigenetic Mechanisms in Down Syndrome Brain

Neurogenesis and neuronal differentiation in the postnatal frontal cortex in Down syndrome

Perspectives on pain in Down syndrome

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