scholarly journals Huntingtin CAG expansion impairs germ layer patterning in synthetic human 2D gastruloids through polarity defects

Development ◽  
2021 ◽  
Vol 148 (19) ◽  
Author(s):  
Szilvia Galgoczi ◽  
Albert Ruzo ◽  
Christian Markopoulos ◽  
Anna Yoney ◽  
Tien Phan-Everson ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Embryonic Stem ◽  
Cag Repeats ◽  
Tgfβ Signaling ◽  
Prodromal Phase ◽  
Tgfβ Receptors ◽  
Cag Expansion ◽  
Human Embryogenesis ◽  
A Cell ◽  
Germ Layer Patterning

ABSTRACT Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expansion of the CAG repeats in the huntingtin gene (HTT). Although HD has been shown to have a developmental component, how early during human embryogenesis the HTT-CAG expansion can cause embryonic defects remains unknown. Here, we demonstrate a specific and highly reproducible CAG length-dependent phenotypic signature in a synthetic model for human gastrulation derived from human embryonic stem cells (hESCs). Specifically, we observed a reduction in the extension of the ectodermal compartment that is associated with enhanced activin signaling. Surprisingly, rather than a cell-autonomous effect, tracking the dynamics of TGFβ signaling demonstrated that HTT-CAG expansion perturbs the spatial restriction of activin response. This is due to defects in the apicobasal polarization in the context of the polarized epithelium of the 2D gastruloid, leading to ectopic subcellular localization of TGFβ receptors. This work refines the earliest developmental window for the prodromal phase of HD to the first 2 weeks of human development, as modeled by our 2D gastruloids.

scholarly journals Huntingtin CAG expansion impairs germ layer patterning in synthetic human gastruloids through polarity defects

2021 ◽  
Author(s):  
Szilvia Galgoczi ◽  
Albert Ruzo ◽  
Christian Markopoulos ◽  
Anna Yoney ◽  
Tien Phan-Everson ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Embryonic Stem ◽  
Cag Repeats ◽  
Tgfβ Signaling ◽  
Prodromal Phase ◽  
Tgfβ Receptors ◽  
Cag Expansion ◽  
Human Embryogenesis ◽  
A Cell ◽  
Germ Layer Patterning

AbstractHuntington’s disease (HD) is a fatal neurodegenerative disorder caused by an expansion of the CAG repeats in the Huntingtin gene (HTT). While HD has been shown to have a developmental component, how early during human embryogenesis the HTT-CAG expansion can cause embryonic defects remains unknown. Here, we demonstrate a specific and highly reproducible CAG length-dependent phenotypic signature in a synthetic model for human gastrulation derived from human embryonic stem cells (hESCs). Specifically, we observed a reduction in the extension of the ectodermal compartment that is associated with enhanced ACTIVIN signaling. Surprisingly, rather than a cell-autonomous effect, tracking the dynamics of TGFβ signaling demonstrated that HTT-CAG expansion perturbs the spatial restriction of ACTIVIN response. This is due to defects in the apicobasal polarization in the context of the polarized epithelium of the gastruloid, leading to ectopic subcellular localization of TGFβ receptors. This work refines the earliest developmental window for the prodromal phase of HD to the first two weeks of human development as modeled by our gastruloids.

scholarly journals Modulation at Age of Onset in Tunisian Huntington Disease Patients: Implication of New Modifier Genes

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Dorra Hmida-Ben Brahim ◽  
Marwa Chourabi ◽  
Sana Ben Amor ◽  
Imed Harrabi ◽  
Saoussen Trabelsi ◽  
...  
Keyword(s):  
Huntington Disease ◽  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Age At Onset ◽  
Specific Effect ◽  
Modifier Genes ◽  
Cag Repeats ◽  
Causative Mutation ◽  
Cag Expansion ◽  
Tunisian Patients

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder. The causative mutation is an expansion of more than 36 CAG repeats in the first exon of IT15 gene. Many studies have shown that the IT15 interacts with several modifier genes to regulate the age at onset (AO) of HD. Our study aims to investigate the implication of CAG expansion and 9 modifiers in the age at onset variance of 15 HD Tunisian patients and to establish the correlation between these modifiers genes and the AO of this disease. Despite the small number of studied patients, this report consists of the first North African study in Huntington disease patients. Our results approve a specific effect of modifiers genes in each population.

scholarly journals Late-onset Huntington’s disease with 40–42 CAG expansion

2019 ◽  
Vol 41 (4) ◽  
pp. 869-876 ◽  
Author(s):  
Elisa Capiluppi ◽  
Luca Romano ◽  
Paola Rebora ◽  
Lorenzo Nanetti ◽  
Anna Castaldo ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Rating Scale ◽  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Late Onset ◽  
Age At Onset ◽  
Clinical Manifestations ◽  
Cag Repeats ◽  
Cag Expansion

Abstract Introduction Huntington’s disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by a CAG expansion greater than 35 in the IT-15 gene. There is an inverse correlation between the number of pathological CAG and the age of onset. However, CAG repeats between 40 and 42 showed a wider onset variation. We aimed to investigate potential clinical differences between patients with age at onset ≥ 60 years (late onset-HD) and patients with age at onset between 30 and 59 years (common-onset HD) in a cohort of patients with the same CAG expansions (40–42). Methods A retrospective analysis of 66 HD patients with 40–41–42 CAG expansion was performed. Patients were investigated with the Unified Huntington’s Disease Rating Scale (subitems I–II–III and Total Functional Capacity, Functional Assessment and Stage of Disease). Data were analysed using χ2, Fisher’s test, t test and Pearson’s correlation coefficient. GENMOD analysis and Kaplan-Meier analysis were used to study the disease progression. Results The age of onset ranged from 39 to 59 years in the CO subgroup, whereas the LO subgroup showed an age of onset from 60 to 73 years. No family history was reported in 31% of the late-onset in comparison with 20% in common-onset HD (p = 0.04). No difference emerged in symptoms of onset, in clinical manifestations and in progression of disease between the two groups. Conclusion There were no clinical differences between CO and LO subgroups with 40–42 CAG expansion. There is a need of further studies on environmental as well genetic variables modifying the age at onset.

scholarly journals Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition

2018 ◽  
Vol 115 (37) ◽  
pp. E8765-E8774 ◽  
Author(s):  
Florian A. Siebzehnrübl ◽  
Kerstin A. Raber ◽  
Yvonne K. Urbach ◽  
Anja Schulze-Krebs ◽  
Fabio Canneva ◽  
...  
Keyword(s):  
Neuronal Differentiation ◽  
Huntington Disease ◽  
Neurodegenerative Disorder ◽  
Cag Repeats ◽  
Interventional Treatment ◽  
Prodromal Phase ◽  
Increased Risk ◽  
Dopaminergic Regulation

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene (HTT). Although mutant HTT is expressed during embryonic development and throughout life, clinical HD usually manifests later in adulthood. A number of studies document neurodevelopmental changes associated with mutant HTT, but whether these are reversible under therapy remains unclear. Here, we identify very early behavioral, molecular, and cellular changes in preweaning transgenic HD rats and mice. Reduced ultrasonic vocalization, loss of prepulse inhibition, and increased risk taking are accompanied by disturbances of dopaminergic regulation in vivo, reduced neuronal differentiation capacity in subventricular zone stem/progenitor cells, and impaired neuronal and oligodendrocyte differentiation of mouse embryo-derived neural stem cells in vitro. Interventional treatment of this early phenotype with the histone deacetylase inhibitor (HDACi) LBH589 led to significant improvement in behavioral changes and markers of dopaminergic neurotransmission and complete reversal of aberrant neuronal differentiation in vitro and in vivo. Our data support the notion that neurodevelopmental changes contribute to the prodromal phase of HD and that early, presymptomatic intervention using HDACi may represent a promising novel treatment approach for HD.

scholarly journals The Temporal Order of DNA Replication Shaped by Mammalian DNA Methyltransferases

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 266
Author(s):  
Shin-ichiro Takebayashi ◽  
Tyrone Ryba ◽  
Kelsey Wimbish ◽  
Takuya Hayakawa ◽  
Morito Sakaue ◽  
...  
Keyword(s):  
Dna Replication ◽  
Temporal Order ◽  
Expression System ◽  
Embryonic Stem ◽  
Replication Timing ◽  
Dna Methyltransferases ◽  
Dna Hypomethylation ◽  
Transcriptional Changes ◽  
A Cell ◽  
Genomic Regions

Multiple epigenetic pathways underlie the temporal order of DNA replication (replication timing) in the contexts of development and disease. DNA methylation by DNA methyltransferases (Dnmts) and downstream chromatin reorganization and transcriptional changes are thought to impact DNA replication, yet this remains to be comprehensively tested. Using cell-based and genome-wide approaches to measure replication timing, we identified a number of genomic regions undergoing subtle but reproducible replication timing changes in various Dnmt-mutant mouse embryonic stem (ES) cell lines that included a cell line with a drug-inducible Dnmt3a2 expression system. Replication timing within pericentromeric heterochromatin (PH) was shown to be correlated with redistribution of H3K27me3 induced by DNA hypomethylation: Later replicating PH coincided with H3K27me3-enriched regions. In contrast, this relationship with H3K27me3 was not evident within chromosomal arm regions undergoing either early-to-late (EtoL) or late-to-early (LtoE) switching of replication timing upon loss of the Dnmts. Interestingly, Dnmt-sensitive transcriptional up- and downregulation frequently coincided with earlier and later shifts in replication timing of the chromosomal arm regions, respectively. Our study revealed the previously unrecognized complex and diverse effects of the Dnmts loss on the mammalian DNA replication landscape.

scholarly journals Cell Type-Specific Role of RNA Nuclease SMG6 in Neurogenesis

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3365
Author(s):  
Gabriela Maria Guerra ◽  
Doreen May ◽  
Torsten Kroll ◽  
Philipp Koch ◽  
Marco Groth ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Cortical Neurons ◽  
Embryonic Stem ◽  
Normal Structure ◽  
Mutant Mice ◽  
Cell Type ◽  
Nonsense Mediated Mrna Decay ◽  
A Cell ◽  
Cell Type Specific

SMG6 is an endonuclease, which cleaves mRNAs during nonsense-mediated mRNA decay (NMD), thereby regulating gene expression and controling mRNA quality. SMG6 has been shown as a differentiation license factor of totipotent embryonic stem cells. To investigate whether it controls the differentiation of lineage-specific pluripotent progenitor cells, we inactivated Smg6 in murine embryonic neural stem cells. Nestin-Cre-mediated deletion of Smg6 in mouse neuroprogenitor cells (NPCs) caused perinatal lethality. Mutant mice brains showed normal structure at E14.5 but great reduction of the cortical NPCs and late-born cortical neurons during later stages of neurogenesis (i.e., E18.5). Smg6 inactivation led to dramatic cell death in ganglionic eminence (GE) and a reduction of interneurons at E14.5. Interestingly, neurosphere assays showed self-renewal defects specifically in interneuron progenitors but not in cortical NPCs. RT-qPCR analysis revealed that the interneuron differentiation regulators Dlx1 and Dlx2 were reduced after Smg6 deletion. Intriguingly, when Smg6 was deleted specifically in cortical and hippocampal progenitors, the mutant mice were viable and showed normal size and architecture of the cortex at E18.5. Thus, SMG6 regulates cell fate in a cell type-specific manner and is more important for neuroprogenitors originating from the GE than for progenitors from the cortex.

Use of Embryonic Stem Cell-Derived Endothelial Cells as a Cell Source to Generate Vessel Structuresin Vitro

2005 ◽  
Vol 11 (3-4) ◽  
pp. 497-505 ◽  
Author(s):  
Kara E. McCloskey ◽  
Meghan E. Gilroy ◽  
Robert M. Nerem
Keyword(s):  
Endothelial Cells ◽  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Cell Source ◽  
A Cell

A cell autonomous function of Brachyury in T/T embryonic stem cell chimaeras

Nature ◽  
1991 ◽  
Vol 353 (6342) ◽  
pp. 348-351 ◽  
Author(s):  
P. Rashbass ◽  
L. A. Cooke ◽  
B. G. Herrmann ◽  
R. S. P. Beddington
Keyword(s):  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Autonomous Function ◽  
A Cell

Stem Cells in Neurodegenerative Disorders - A broad Overview

2021 ◽  
Author(s):  
Fariha Khaliq
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Pluripotent Stem Cells ◽  
Neurodegenerative Disorder ◽  
Human Fibroblasts ◽  
Embryonic Stem ◽  
Different Types ◽  
Induced Pluripotent

Stem cell therapy is an approach to use cells that have the ability of self-renewal and to differentiate into different types of functional cells that are obtained from embryo and other postnatal sources to treat multiple disorders. These cells can be differentiated into different types of stem cells based on their specific characteristics to be totipotent, unipotent, multipotent or pluripotent. As potential therapy, pluripotent stem cells are considered to be the most interesting as they can be differentiated into different type of cells with similar characteristics as embryonic stem cells. Induced pluripotent stem cells (iPSCs) are adult cells that are reprogrammed genetically into stem cells from human fibroblasts through expressing genes and transcription factors at different time intervals. In this review, we will discuss the applications of stem cell therapy using iPSCs technology in treating neurodegenerative disorder such that Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS). We have also broadly highlighted the significance of pluripotent stem cells in stem cell therapy.

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