Genetics and Neurobiology of Down Syndrome

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GENETICS AND NEUROBIOLOGY OF DOWN SYNDROME 
GENETICS AND NEUROBIOLOGY OF DOWN SYNDROMEBANI BANDANA GANGULYMGM NEW BOMBAY HOSPITAL, VASHI, NAVI MUMBAI, INDIAMGM INSTITU ...
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Contents
An overview of this book
Preface
1 - Down syndrome: history and overview
1. History
2. Incidence
3. Sex ratio
4. Recurrence
5. What other names do people use for Down syndrome?
6. Can Down syndrome be inherited?
7. Secular trends and racial and ethnic variation
References
2 - Implications of trisomy 21 on congenital features and health aspects
1. Introduction
2. Phenotypic features and systemic complications of Down syndrome
2.1 Craniofacial malformations
2.2 Learning, memory, brain development, and function
2.3 Alzheimer disease
2.4 Epilepsy
2.5 Immune systems
2.6 SARS CoV-2 infection
2.7 Hematology
2.8 Congenital heart defects
2.9 Sleep apnea
2.10 Thyroid dysfunction
2.11 Gastrointestinal complications
2.12 Neurology
2.13 Mental health
2.14 Atlantoaxial instability
2.15 Ophthalmology and otolaryngology
3. Life-span of individuals with Down syndrome
4. Attention to be paid for health monitoring of Down syndrome
4.1 At birth
4.2 At childhood and adult age
5. Fertility of Down syndrome
References
3 - Chromosomal etiology of Down syndrome: genesis of trisomy 21
1. Introduction
2. Chromosome 21
2.1 Occurrence of trisomy 21
2.2 Classical Down syndrome
2.3 Variant Down syndrome
2.3.1 Mosaic Down syndrome
2.3.2 Trisomy 21 with Robertsonian translocation
2.3.3 Balanced translocation
2.3.4 Partial duplication of chromosome 21
3. Genes of HSA21
References
4 - Possible factors contributing to chromosomal nondisjunction and formation of trisomic HSA21
1. Introduction
2. Factors that can cause nondisjunction of chromosomes
2.1 Age factor
2.2 Antenatal complexity
2.3 Effects of environment, occupation, and lifestyle
2.4 Meiotic recombination
References
5 - Prevention of Down syndrome: genetic counseling, prenatal screening, testing, awareness, attitude, and socio-cu ...
1. Introduction
2. Genetic counseling
3. Preconception screening and prenatal diagnosis
3.1 Anticipated issues of prenatal screening
4. The attitude and awareness of the parents
4.1 Unawareness: a blessing in disguise
4.2 What would be the impact of their unawareness?
5. Ethical aspects
6. Policies and guidelines
7. Public health point of view toward Down syndrome
7.1 Public Health Department's support
8. Socio-cultural aspects of Down syndrome
References
6 - Gene-dosage imbalance due to trisomic HSA21 and genotype–phenotype association in Down syndrome
1. Introduction
2. Gene-dosage imbalance
3. Genotype–phenotype correlation
3.1 Genomic variability for DS phenotypes
3.2 Allelic variation on HSA21
3.3 Modifier genes
3.4 Coincidental small effects
3.5 Interaction of genes for DS phenotypes
4. Transcriptomes of trisomy 21
5. Proteomes of trisomy 21
5.1 Proteomes detected in trisomic fetus
5.2 Proteomic changes of chronic autoinflammation in people with DS
5.3 Proteins and growth factor receptors involved in neurogenesis
References
7 - Development of specific phenotypes and genetic consequences in Down syndrome: malformations in craniofacial and ...
1. Introduction
2. Genes of developmental stages
3. Trisomic segments in mouse models: genotyping of DS phenotypes
4. Craniofacial alterations in Down syndrome
4.1 Hypotheses on craniofacial malformations
4.2 Development of craniofacial expressions
4.3 Implication of dosage sensitivity on craniofacial expression
4.4 Developmental algorithm of craniofacial structure in trisomic mice
5. Cardiac defects in Down syndrome
5.1 Morphogenesis of heart defects and contribution of Creld1
5.2 Genotyping of heart defects in Down syndrome
5.3 Development of heart in trisomic DS mouse models
6. Cognitive development and learning and memory deficits
6.1 Morphogenesis of cognitive impairment
6.2 Genotype of learning and memory deficits
6.3 Proteins linked to cognitive performance
7. Genetics of leukemia in Down syndrome
7.1 Megakaryopoiesis and transient myeloproliferative disorders in Down syndrome
7.2 ALL in Down syndrome (DS-ALL)
7.3 Gene expression in mouse models for DS leukemia
8. Less of solid tumors in Down syndrome
9. Genes of motor control and hypotonia
10. Trisomic HSA21 genes and hypocomplementia
11. Concluding remarks
References
8 - Triplicated HSA21 genes and mtDNA on mitochondrial dysfunction: consequential changes in mitochondrial dynamics ...
1. Introduction
2. Mitochondrial dynamics and genome
3. Alterations in mitochondrial dynamics in DS
4. Regulation of mitochondrial bioenergetics in DS
5. Mitochrondrial dysfunction in DS: increased oxidative stress and inflammation
6. Triplicated HSA21 genes: implication on mitochondrial biogenesis and function
6.1 Trisomic HSA21 genes involved in mitochondrial dysfunction
6.1.1 The co-activator PGC-1α
6.1.2 The nuclear receptor interacting protein 1
6.1.3 Interaction of PGC-1α and NRIP1
6.1.4 SUMO3
6.1.5 DYRK1A
6.1.6 RCAN1
6.1.7 PREP1
6.1.8 Humanin
6.1.9 SOD1
6.1.10 S100B
6.1.11 Cystathionine-β-synthase
6.1.12 MicroRNA
6.2 Mitochondrial biogenesis in DS
References
9 - Disarrayed mitochondrial function on pathobiology in Down syndrome and targeted therapeutics
1. Introduction
2. Diseases caused by mitochondrial dysfunction
2.1 Heart defects and mitochondria
2.1.1 Association of RCAN1 and trisomic cardiomyocytes
2.1.2 The role of mitochondrial Ca2+ homeostasis inducing cell death
2.2 Mitochondria and hypotonia
2.3 Mitochondria and type 2 diabetes and obesity
2.4 Mitochondria and immune disorders
2.5 Aging
2.6 Mitochondrial dysfunction on neurodegeneration and Alzheimer disease
3. Oxidative stress: an indication of adaptive response in DS
4. Clearance of dead cells: autophagy and mitophagy in DS
5. Targeted therapies for restoration of mitochondrial network in DS
5.1 Polyphenols
5.1.1 Epigallocatechin-3-gallate
5.1.2 Resveratrol
5.1.3 Omega-3 fatty acids
5.1.4 Metformin
5.2 Coenzyme Q10, antioxidants, and melatonin
5.3 Other pharmacologic agents
6. Concluding remarks
References
10 - Gene-dosage imbalance and altered neurogenesis in Down syndrome
1. Introduction
2. Developmental consequences of brain in DS
3. Genetic implication of neurologic alterations in DS
3.1 Dysregulation of gene expression and alteration in neurogenesis
3.2 Deregulated pathways involved in neurogenesis in trisomic cells
3.3 Growth factor receptors, proteins, and altered neurogenesis in DS
4. Mitochondrial control of neural progenitor cells
5. Concluding remarks
References
11 - Imbalance in glutamatergic and GABAergic transmission in Down syndrome and therapeutic targets
1. Introduction
2. Neurotransmission in DS brain
2.1 Generation and migration of GABAergic neurons
2.2 Synthesis and shunting of GABA transmission
2.3 Molecular ontogeny of glutamic acid decarboxylase
2.4 Migration and settlement of GABAergic neurons
3. The GABAergic receptors and ontogenic changes
3.1 GABA-A receptors
3.2 GABA-B receptors
4. Glutamatergic and GABAergic systems during development
4.1 Chloride-mediated inhibition of motoneuron maturation
4.2 Interplay of KCC2 and NKCC1 and mechanism of GABA polarization
4.3 Phasic and tonic inhibition
4.4 Transition of GABA expression during embryonic life
4.5 Maturation of the GABAergic neurotransmission
4.6 Functions of GABA-AR and GABA-BR on synaptic plasticity
5. GABA signaling in trisomic condition
5.1 Trisomy HSA21 and GABA-A signaling
5.2 Trisomy HSA21 and GABA-B signaling
6. Alterations of GABAergic circuits in DS model and neurodevelopmental disorders
6.1 GABA signaling in DS patient–derived stem cells
7. Perspectives on therapeutics of GABAergic transmission
7.1 Modulation of synaptic plasticity and GABA signaling in DS
7.2 Therapeutics for GABAergic signaling in DS
7.3 GABA transmission as a pharmacological target to rescue cognitive deficits in DS
7.4 Modulation of GABA/BDNF mechanism
7.5 Modulators of excitatory deficits in DS
7.6 Modulation of GABA in DS neurodevelopment and critical period plasticity
7.7 GABA alteration for other DS symptoms
8. Concluding remarks
References
12 - Alzheimer disease and neuroinflammation in Down syndrome: Effects of gene dosage and therapeutics
1. Introduction
2. Preclinical changes of cognitive performance
3. Dementia in AD
4. Bio-markers of AD
4.1 Mechanism of Aβ processing, cleavage Aβ, degradation, and clearance in the brain
4.2 Soluble Aβ oligomers in DS
4.3 Intracellular Aβ in DS
4.4 Senile Aβ plaques
4.5 Oxidative stress and AD in Down syndrome
4.6 Mitochondrial dysfunction and Aβ processing
4.7 Tau phosphorylation and neurofibrillary tangles in DS
4.8 Neuronal loss in DS
4.9 Exosomal factors of AD
5. Age-related consequences of AD pathogenesis
6. Genes involved in neuropathologic events in DSAD
7. Ubiquitinylation and proteasome system of AD development
8. Perspectives of neuroinflammation in DSAD
8.1 Neuroinflammation in AD
8.2 Neuroinflammatory markers of DSAD
8.3 Microglial changes associated with neuroinflammation in DSAD
9. Genes of neuroinflammation in Down syndrome
10. Therapeutics of AD management in DS
10.1 Clinical trials
10.2 Practical concerns of clinical trials
10.3 Therapeutic intervention in DS models
10.3.1 Mouse models
10.3.2 Cellular models
10.4 Therapeutics on mitochondrial dysfunction and oxidative stress in DSAD
10.5 Exosomes as novel therapeutics for AD
11. Conclusion and future direction
References
13 - MicroRNAs and epigenetic signatures in Down syndrome
1. Introduction
2. MicroRNAs and biogenesis
2.1 Noncoding RNAs
2.2 Long noncoding RNAs
3. HSA21-MicroRNAs in Down syndrome
4. Disease consequences of HSA21-miRNAs
4.1 Association of HSA21-miRNAs on mitochondrial output in DS
5. Association of other non-HSA21 miRNAs with HSA21-miRNAs
6. Drug targets of miRNAs
7. Perspectives of microRNAs in prenatal diagnosis of DS
8. Spectrum of epigenetic expression in DS
8.1 Epigenetics of ncRNAs
9. DS phenotypes associated with epigenetic modulation
10. Therapeutic targets of epigenetic expression
11. Concluding remarks
References
14 - In vivo and in vitro models for research on Down syndrome
1. Introduction
2. Models of DS research
3. Mouse models in DS research
3.1 Ts16
3.2 Ts43H (Ts(1617)43H)
3.3 Ts65Dn (Ts(1716)65Dn)
3.4 Ts1Cje (Ts12; 16C-tel)1Cje)
3.5 Ts2Cje (Ts[Rb(12.Ts171665Dn)]2Cje)
3.6 Ts1Rhr and related mice
3.7 Ts1Yah
3.8 The relational context of the Ts65Dn, Ts1Cje, and Ts2Cje models
3.9 Other mouse models of DS with trisomy or monosomy for the entire chromosomal regions of MMU16, MMU17, and MMU10 syntenic to ...
3.10 Transchromosomal model: Tc1
3.11 Transgenic mice
3.11.1 Transgenic mice to study intellectual disability and altered brain function in DS individuals
3.11.1.1 APP
3.11.1.2 RCAN1
3.11.1.3 SYNJ1
3.11.2 Transgenic mouse models to study the cancer spectrum in people with DS
3.11.2.1 ETS2
3.11.2.2 RUNX1
3.12 Mouse models with genes inactivated by targeted mutagenesis
3.13 Gene-knockout models to study intellectual disability/brain function
3.13.1 APP
3.13.2 RCAN1
3.13.3 SYNJ1
3.14 Knockout mice developed for understanding the cancer spectrum in DS
3.14.1 ERG
3.14.2 ETS2
3.14.3 RUNX1
4. iPSCs with HSA21 as model in DS research
5. Organoids (iPSC-based) as chimeric models to study neurogenesis in DS
6. Technical challenges of DS modeling and engineering of genes of interest
6.1 Developing DS models
6.2 Biological differences between mice and humans
6.3 Compendium of DS models
7. HSA21 synteny studied on other models
7.1 Rat models (Rattus norvegicus)
7.2 Saccharomyces as a model for understanding the global effects of aneuploidy
7.3 Worm orthologs as a model for understanding neurodevelopment
7.4 HSA21 orthologs in Drosophila
7.5 Zebrafish as a vertebrate system to screen HSA21 effects of DS
8. Models for pharmaceutical developments for DS
9. Conclusion and perspectives
References
Index
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