scholarly journals Down syndrome fibroblasts exhibit diminished autophagic clearance and endosomal dysfunction after serum starvation

2018 ◽  
Author(s):  
Stefanos Aivazidis ◽  
Abhilasha Jain ◽  
Colin C. Anderson ◽  
David J. Orlicky ◽  
Abhishek K. Rauniyar ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Protein Quality ◽  
Genetic Disorder ◽  
Chromosome 21 ◽  
Serum Starvation ◽  
Autophagic Flux ◽  
Recycling Endosome ◽  
Recycling Endosomes ◽  
Early Endosomes ◽  
Endosomal System

AbstractDown syndrome (DS) is a genetic disorder caused by trisomy of chromosome 21 (Tri21). This unbalanced karyotype has the ability to produce proteotoxic stress and dysfunction of the proteostasis network (PN), which are mechanistically associated with several comorbidities found in the DS phenotype. Autophagy is the cellular process responsible for bulk protein degradation and its impairment could negatively impact protein quality control. Based on our previous observations of PN disruption in DS, we investigated possible dysfunction of the autophagic machinery in human DS fibroblasts. Both euploid (CTL) and DS fibroblasts induced autophagy successfully through serum starvation (SS), as evidenced by increased LC3-II abundance in CTL and DS. However, DS cells displayed evidence of autophagolysosome (AL) accumulation and impaired clearance of autophagosome cargo, e.g. accumulation of p62 and NBR1. Similar observations were also present in DS cells from multiple differentiation stages, implicating impeded autophagic degradation as a possible early pathologic mechanism in DS. Lysosomal pH and cathepsin B proteolytic activity were found to not differ in CTL and DS fibroblasts after SS, indicating that lysosomal dysfunction did not appear to contribute to unsuccessful autophagic clearance. Based on these results, we hypothesized that possible interference of the endosomal system with autophagy results in autophagosome fusion with endosomal vesicles and negatively impacts degradation. Consistent with this hypothesis, we observed increased abundance of the recycling endosome marker, Rab11, after SS in DS fibroblasts. Further, colocalization of autophagosome markers with resident proteins of early endosomes, late endosomes and recycling endosomes (Rab11) further support our hypothesis. In summary, our work is consistent with impairment of autophagic flux and general PN dysfunction as candidate mechanisms for pathology in DS.

scholarly journals A TOCA/CDC-42/PAR/WAVE functional module required for retrograde endocytic recycling

2015 ◽  
Vol 112 (12) ◽  
pp. E1443-E1452 ◽  
Author(s):  
Zhiyong Bai ◽  
Barth D. Grant
Keyword(s):  
Functional Module ◽  
Small Gtpase ◽  
Recycling Endosome ◽  
Vesicle Budding ◽  
Recycling Endosomes ◽  
Physiological Importance ◽  
Golgi Transport ◽  
Early Endosomes ◽  
Cargo Proteins ◽  
Signaling Receptors

Endosome-to-Golgi transport is required for the function of many key membrane proteins and lipids, including signaling receptors, small-molecule transporters, and adhesion proteins. The retromer complex is well-known for its role in cargo sorting and vesicle budding from early endosomes, in most cases leading to cargo fusion with the trans-Golgi network (TGN). Transport from recycling endosomes to the TGN has also been reported, but much less is understood about the molecules that mediate this transport step. Here we provide evidence that the F-BAR domain proteins TOCA-1 and TOCA-2 (Transducer of Cdc42 dependent actin assembly), the small GTPase CDC-42 (Cell division control protein 42), associated polarity proteins PAR-6 (Partitioning defective 6) and PKC-3/atypical protein kinase C, and the WAVE actin nucleation complex mediate the transport of MIG-14/Wls and TGN-38/TGN38 cargo proteins from the recycling endosome to the TGN in Caenorhabditis elegans. Our results indicate that CDC-42, the TOCA proteins, and the WAVE component WVE-1 are enriched on RME-1–positive recycling endosomes in the intestine, unlike retromer components that act on early endosomes. Furthermore, we find that retrograde cargo TGN-38 is trapped in early endosomes after depletion of SNX-3 (a retromer component) but is mainly trapped in recycling endosomes after depletion of CDC-42, indicating that the CDC-42–associated complex functions after retromer in a distinct organelle. Thus, we identify a group of interacting proteins that mediate retrograde recycling, and link these proteins to a poorly understood trafficking step, recycling endosome-to-Golgi transport. We also provide evidence for the physiological importance of this pathway in WNT signaling.

scholarly journals Gambaran Erupsi Gigi Permanen pada Anak Sindrom Down Usia 10-16 Tahun di Sekolah Luar Biasa Kabupaten Jember

2018 ◽  
Vol 8 (1) ◽  
pp. 8
Author(s):  
Loly Anastasya Sinaga ◽  
Dwi Kartika Apriyono ◽  
Masniari Novita
Keyword(s):  
Down Syndrome ◽  
Special Needs ◽  
Physical Characteristic ◽  
Trisomy 21 ◽  
Genetic Disorder ◽  
Extra Chromosome ◽  
Descriptive Study ◽  
Chromosome 21 ◽  
Permanent Teeth ◽  
Intellectual Abilities

Background: Down Syndrome is a genetic disorder that occurs because of chromosome 21 has three chromosome (trisomy 21). The extra chromosome changes the genetic balance, physical characteristic, intellectual abilities, and physiological body function. Tooth eruption in Down Syndrome children typically delayed in both the timing and sequence of eruption up to two or three years. Objective: To observe the permanent teeth eruption in Down syndrome children at age 10-16 years old, boys and girls in Special Needs School in Jember. Materials and Methods: This research was a descriptive study with 7 subjects. Each subject was examined then calculated teeth that had emerged or functionally eruption with articualting paper. Result and Conclusion:  Both permanent teeth that is still partially erupted tooth (emerged/ EM) and had erupted perfectly (functionally eruption/ FE) delayed in eruption in Down Syndrome boys and girls at age 10-16 years old.

scholarly journals Bioinformatics Investigation and Contribution of Other Chromosomes Besides Chromosome 21 in the Risk of Down Syndrome Development

2021 ◽  
Vol 12 (1) ◽  
pp. 79-88
Author(s):  
Mona Zamanian Azodi ◽  
◽  
Mostafa Rezaei Tavirani ◽  
Majid Rezaei Tavirani ◽  
Mohammad Rostami Nejad ◽  
...  
Keyword(s):  
Gene Expression ◽  
Down Syndrome ◽  
Gene Expression Profile ◽  
Clinical Studies ◽  
Genetic Disorder ◽  
Research Topic ◽  
Chromosome 21 ◽  
Network Centrality ◽  
Microarray Study ◽  
Molecular Studies

Introduction: Down syndrome as a genetic disorder is a popular research topic in molecular studies. One way to study Down syndrome is via bioinformatics. Methods: In this study, a gene expression profile from a microarray study was selected for more investigation. Results: The study of Down syndrome patients shows specific genes with differential expression and network centrality properties. These genes are introduced as RHOA, FGF2, FYN, and CD44, and their level of expression is high in these patients. Conclusion: This study suggests that besides chromosomes 21, there are additional contributing chromosomes to the risk of Down syndrome development. Besides, these genes could be used for clinical studies after more analysis.

scholarly journals Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors

2019 ◽  
Author(s):  
JiaJie Teoh ◽  
Narayan Subramanian ◽  
Maria Elena Pero ◽  
Francesca Bartolini ◽  
Ariadna Amador ◽  
...  
Keyword(s):  
Cell Body ◽  
Membrane Surface ◽  
Seizure Threshold ◽  
List Type ◽  
Recycling Endosome ◽  
Neuron Culture ◽  
Recycling Endosomes ◽  
Neuronal Inhibition ◽  
Early Endosomes ◽  
Hippocampal Neuron Culture

AbstractARFGEF1 encodes a guanine exchange factor involved in intracellular vesicle trafficking, and is a candidate gene for childhood genetic epilepsies. To model ARFGEF1 haploinsufficiency observed in a recent Lennox Gastaut Syndrome patient, we studied a frameshift mutation (Arfgef1fs) in mice. Arfgef1fs/+ pups exhibit signs of developmental delay, and Arfgef1fs/+ adults have a significantly decreased threshold to induced seizures but do not experience spontaneous seizures. Histologically, the Arfgef1fs/+ brain exhibits a disruption in the apical lining of the dentate gyrus and altered spine morphology of deep layer neurons. In primary hippocampal neuron culture, dendritic surface and synaptic but not total GABAA receptors (GABAAR) are reduced in Arfgef1fs/+ neurons with an accompanying decrease in GABAAR-containing recycling endosomes in cell body. Arfgef1fs/+ neurons also display differences in the relative ratio of Arf6+:Rab11+:TrfR+ recycling endosomes. Although the GABAAR-containing early endosomes in Arfgef1fs/+ neurons are comparable to wildtype, Arfgef1fs/+ neurons show an increase in GABAAR-containing lysosomes in dendrite and cell body. Together, the altered endosome composition and decreased neuronal surface GABAAR results suggests a mechanism whereby impaired neuronal inhibition leads to seizure susceptibility.HighlightsArfgef1fs/+ mice have lower seizure threshold but no spontaneous seizure.Arfgef1fs/+ neurons show reduced dendritic surface GABAAR.Arfgef1fs/+ neurons have decreased GABAAR-containing recycling endosome accompanied with an increase in GABAAR-containing lysosomes.

scholarly journals Novel DYRK1A Inhibitor Rescues Learning and Memory Deficits in a Mouse Model of Down Syndrome

2021 ◽  
Vol 14 (11) ◽  
pp. 1170
Author(s):  
Wenche Stensen ◽  
Ulli Rothweiler ◽  
Richard Alan Engh ◽  
Melissa R. Stasko ◽  
Ilya Bederman ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Cognitive Deficits ◽  
Genetic Disorder ◽  
Treatment Options ◽  
Chromosome 21 ◽  
The Novel ◽  
Behavioral Challenges ◽  
Early Onset Alzheimer’S Disease ◽  
Encoding Gene ◽  
Complex Genetic Disorder

Down syndrome (DS) is a complex genetic disorder associated with substantial physical, cognitive, and behavioral challenges. Due to better treatment options for the physical co-morbidities of DS, the life expectancy of individuals with DS is beginning to approach that of the general population. However, the cognitive deficits seen in individuals with DS still cannot be addressed pharmacologically. In young individuals with DS, the level of intellectual disability varies from mild to severe, but cognitive ability generally decreases with increasing age, and all individuals with DS have early onset Alzheimer’s disease (AD) pathology by the age of 40. The present study introduces a novel inhibitor for the protein kinase DYRK1A, a key controlling kinase whose encoding gene is located on chromosome 21. The novel inhibitor is well characterized for use in mouse models and thus represents a valuable tool compound for further DYRK1A research.

Down Syndrome from a Neurodevelopmental Perspective

2016 ◽  
Author(s):  
Hana D’Souza ◽  
Jamie Edgin ◽  
Annette Karmiloff-Smith
Keyword(s):  
Down Syndrome ◽  
Individual Differences ◽  
Trisomy 21 ◽  
Genetic Disorder ◽  
Developmental Time ◽  
Receptive Vocabulary ◽  
Chromosome 21 ◽  
Typically Developing ◽  
Altered Expression ◽  
Wide Range

This is an advance summary of a forthcoming article in the Oxford Research Encyclopedia of Psychology. Please check back later for the full article. Down syndrome (DS; trisomy 21) is the most common genetic disorder associated with intellectual disability. It occurs in one out of every 700 to 1,000 live births. DS is caused by trisomy of human chromosome 21, which results in the altered expression of over 300 genes. This neurodevelopmental syndrome is characterized by distinctive facial dysmorphology and an uneven cognitive phenotype including relative strengths and weaknesses. Relative strengths include visual processing, receptive vocabulary, and social-emotional functioning (though performance in these domains generally falls below the level expected for typically developing individuals). Relative weaknesses include verbal working memory, expressive language, and motor ability. However, the phenotype of individuals with DS is far from homogeneous, and a wide range of individual differences is present at every level of description. On the genetic level, the trisomy can occur through different mechanisms at distinct developmental time points, and the expression of trisomy 21 may be modulated by different genes across individuals. On the level of the brain, individual differences in brain structure and/or function correlate with variation in cognition and behavior, including communication skills. Large individual differences can also be observed on the cognitive level. For example, while some toddlers with DS are nonverbal, others reach expressive vocabulary levels close to those of typically developing children. A wide range of individual differences has also been reported in other areas, including the motor domain, sleep, parent-child interaction, and medical and psychiatric comorbidities. In order to understand a neurodevelopmental syndrome such as DS, it is crucial to consider individual variations at multiple levels of description and the interactions between them over developmental time. A more complex, dynamic view that goes beyond a description of DS as a homogenous group is thus required.

scholarly journals Síndrome de down: facilidades, dificuldades e apoio encontrado pelos pais / Down syndrome: facilities, dificulties and support found by parents

2017 ◽  
Vol 7 (2) ◽  
pp. 23-29
Author(s):  
Mayra Cristina Martins dos Santos ◽  
Ana Camila Batista ◽  
Ivandira Anselmo Ribeiro Simões
Keyword(s):  
Down Syndrome ◽  
Mental Retardation ◽  
Exploratory Study ◽  
Social Representations ◽  
Genetic Disorder ◽  
Structured Interview ◽  
Chromosome 21 ◽  
Professional Characteristics ◽  
Qualitative Descriptive ◽  
Answering Questions

Introdução: A síndrome de Down (SD) é um distúrbio genético, devido à presença adicional de um cromossomo 21 nas células de seu portador e que causa um retardo mental de vários graus. Objetivos: Identificar quais as dificuldades e facilidades que os pais tiveram na criação de seus filhos com a SD e conhecer que tipos de apoio os pais dos portadores da SD receberam. Métodos: Pesquisa do tipo qualitativa, descritiva e exploratória. Para a análise e interpretação dos dados utilizou-se a técnica do Discurso do Sujeito Coletivo, que tem como base as Teorias das Representações Sociais. O local do estudo foi na APAE de Itajubá. A amostragem foi por conveniência; a amostra foi inicialmente constituída por 30 participantes que possuem filhos com a SD. No entanto, responderam à pergunta semiestruturada 14 participantes, os demais alegaram não ter interesse e estarem cansados em responder perguntas relacionadas ao tema; assim a amostra constou de 14 participantes. Os instrumentos utilizados na coleta de dados foram dois: um roteiro de entrevista semiestruturada e outro que contempla informações relacionadas à caracterização pessoal e profissional dos participantes do estudo. Resultados: As Ideias Centrais (IC) quanto à questão relacionada às facilidades foram: APAE, amigos, nenhuma e psicóloga. Quanto às dificuldades, foram: não teve, muitas dificuldades, não poder estudar em outra escola e saber até onde iria chegar. Já quanto ao apoio, foram as seguintes: APAE e comunidade. Conclusão: Observou-se que o desenvolvimento da pessoa portadora de SD está fortemente relacionado com a APAE, pois foi a própria APAE que os acolheu e os ajudou a conseguirem o que almejaram.Palavras-chave: Síndrome de down; Pais; EnfermagemABSTRACTIntroduction: The Down Syndrome (DS) is a genetic disorder characterized by the additional presence of the chromosome 21 in the patients´ cells and that causes a spectrum of mental retardation. Aims: To identify which difficulties and facilities parents have in raising their children with DS and know what kind of support the parents of DS patients received. Methods: It is a qualitative, descriptive, and exploratory study. For analysis and interpretation of the data it was used the Collective subject discourse technique, which is based on the Theory of Social Representations. The study site was the APAE of Itajubá. Sampling was purposeful; the sample was initially composed of 30 participants who have children with DS. However, only 14 participants answered the semi-structured questions, for the others claimed to have no interest and were tired of answering questions related to the topic; therefore the sample consisted of 14 participants. The instruments used in data collection were two: one set of semi-structured interview questions and another that included information related to the personal and professional characteristics of the participants. Results: The Central Ideas (CI) regarding the question related to the facilities were: APAE, friends, none, and psychologist. As for the difficulties, they were as following: none, many difficulties, not to study in another school and how far they would go. As for the support, they were: APAE and community. Conclusion: It was observed that the development of the DS carrier person is strongly related to APAE because it is the institution that welcomed them and helped them get what they longed for.Keywords: Down syndrome; Parents; Nursing

scholarly journals Evaluation of postural control in children and adolescents with down syndrome aged eight to twelve years old

2018 ◽  
Vol 28 (1) ◽  
pp. 50
Author(s):  
Jessica Cristina Leite ◽  
Jéssica Caroliny de Jesus Neves ◽  
Leonardo George Victorio Vitor ◽  
Dirce Shizuko Fujisawa
Keyword(s):  
Down Syndrome ◽  
Nutritional Status ◽  
Postural Control ◽  
Children And Adolescents ◽  
Center Of Pressure ◽  
Genetic Disorder ◽  
Statistical Significance ◽  
Chromosome 21 ◽  
Cross Sectional ◽  
Convenience Sample

Introduction: Down Syndrome is a genetic disorder caused by the presence of the third copy of chromosome 21 (total or partial). The syndrome occurs in approximately one out of every 700 – 1000 newborns per year. Objective:To analyze postural control (PC) of children and adolescents with Down Syndrome (DS) and to compare differences regarding age, sex, nutritional status, and physical activity (PA) levels. Methods: In this cross-sectional study, a convenience sample composed of 21 children and adolescents (9 girls) was categorized according to age: G1 (8 to 9 years old; n = 8), G2 (10 years old; n = 7), and G3 (11 to 12 years old; n = 6), Score-Z: eutrophic (n = 9) and overweight (n = 12), and PA level: practitioners (n = 7) and non-practitioners (n = 14). PC was assessed in the force platform (FP), in the standing position, with feet together during 30 seconds. The variables analyzed were the center of pressure area (COP) and the mean velocities of anteroposterior and mediolateral oscillation (VEL-AP and VEL-ML). Shapiro-Wilk test was used to test the normality of data. Kruskal-Wallis, Dunn’s, and Mann Whitney tests were performed to analyze associations with PC. Statistical significance was set at p<0.05. Results: The median COP, VEL-AP and VEL-ML were 3.55 [2.13 – 6.82] , 2.81 [2.32 – 3.16], and 2.98 [2.42 – 3.43], respectively. There were no differences in PC regarding sex, body mass index and PA level. The adolescents in G3 presented lower values of VEL-AP (G1=2,88 [2,82 – 3,21]; G2= 2,94 [2,35 – 3,39]; G3= 2,27 [2 – 2,3]) and VEL-ML (G1= 3,22 [3,14 – 3,68]; G2= 2,91 [2,52 – 3,63]; G3= 2,34 [2,1 – 2,39]). Conclusion: Sex, nutritional status, and PA level did not affect COP area and AP-VEL and ML-VEL. However, strategies were affected by age, as observed by differences in velocity, but did not affect the COP area.  

scholarly journals Aberrant calcium signaling in astrocytes inhibits neuronal excitability in a human Down syndrome stem cell model

2018 ◽  
Author(s):  
Grace O. Mizuno ◽  
Yinxue Wang ◽  
Guilai Shi ◽  
Yizhi Wang ◽  
Junqing Sun ◽  
...  
Keyword(s):  
Neural Networks ◽  
Stem Cells ◽  
Down Syndrome ◽  
Cognitive Impairment ◽  
Calcium Imaging ◽  
Neuronal Excitability ◽  
Genetic Disorder ◽  
Chromosome 21 ◽  
Significant Implication ◽  
Functional Defects

AbstractDown syndrome (DS) is a devastating genetic disorder causing severe cognitive impairment. The staggering array of effects associated with an extra copy of human chromosome 21 (HSA21) complicates mechanistic understanding of DS pathophysiology. We developed an in vitro system to examine the interplay of neurons and astrocytes in a fully recapitulated HSA21 trisomy model differentiated from DS patient-derived induced pluripotent stem cells (iPSCs). By combining calcium imaging with genetic approaches, we utilized this system to investigate the functional defects of DS astroglia and their effects on neuronal excitability. We found that, compared with control isogenic astroglia, DS astroglia exhibited more-frequent spontaneous calcium fluctuations, which reduced the excitability of co-cultured neurons. DS astrocytes exerted this effect on both DS and healthy neurons. Neuronal activity could be rescued by abolishing astrocytic spontaneous calcium activity either chemically by blocking adenosine-mediated astrocyte–neuron signaling or genetically by knockdown of inositol triphosphate (IP3) receptors or S100β, a calcium binding protein coded on HSA21. Our results suggest a novel mechanism by which DS alters the function of astrocytes, which subsequently disturbs neuronal excitability. Furthermore, our study establishes an all-optical neurophysiological platform for studying human neuron-astrocyte interactions associated with neurological disorders.Significant statementDown syndrome (DS) is the most common genetic disorder caused by trisomy of chromosome 21 (HSA21). Problems with cognitive impairment, have not been properly addressed due to the inability to fully recapitulate HSA21, which is further confounded by the snapshot views of morphological changes of brain cells in isolation obtained from current studies. The brain develops neural networks consisting of neurons and glial cells that work together. To understand how DS affects the neural networks, we used DS patient-derived stem cells and calcium imaging to investigate functional defects of DS astrocytes and their effects on neuronal excitability. Our study has significant implication in understanding functional defects during brain development underlying DS.

scholarly journals Feasibility and Reliability of a Physical Fitness Test Battery in Individuals with Down Syndrome

2019 ◽  
Vol 16 (15) ◽  
pp. 2685 ◽  
Author(s):  
Ruth Cabeza-Ruiz ◽  
Francisco Javier Alcántara-Cordero ◽  
Isaac Ruiz-Gavilán ◽  
Antonio Manuel Sánchez-López
Keyword(s):  
Down Syndrome ◽  
Physical Fitness ◽  
Genetic Disorder ◽  
Cross Sectional Study ◽  
Chromosome 21 ◽  
Extra Copy ◽  
Timed Up And Go ◽  
Cross Sectional ◽  
Physical Fitness Test ◽  
Motor Fitness

Background: Down syndrome (DS) is a genetic disorder that occurs because of an abnormal division between cells that results in an extra copy of chromosome 21. Some studies show that physical exercise in people with DS increases some cognitive capacities, such as memory, and improves the quality of life. Aim: The main aim of this study was to perform an analysis of the reliability and feasibility of the SAMU-Disability Fitness (DISFIT) battery in adults with DS. Methods: A cross-sectional study with a test–retest design was performed in a maximum interval of 2 weeks in 37 subjects (11 women and 26 men) aged between 21 and 58 years old with DS. Eight field-based fitness tests were proposed to assess the physical fitness (PF) of adults with DS: Body Mass Index (BMI), Waist Circumference (WC), the Timed Up and Go test (TUG), the Deep Trunk Flexibility test (DTF), the Hand Grip test (HG), the Timed Stand Test (TST), the 30-s Sit-Up (SUP) and the 6-Min Walk Test (6MWT). Results: The intra-class correlation coefficient (ICC) in all the tests was good and high (>0.80), except for the 6MWT, whose reliability was fair. Conclusion: The SAMU-DISFIT battery is a reliable and feasible physical fitness battery which has been created with the purpose of establishing tests which measure the four basic components of PF (flexibility, cardiorespiratory fitness, musculoskeletal fitness and motor fitness) in adults with DS.

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