Prenatal and Postnatal Pharmacotherapy in Down Syndrome: The Search to Prevent or Ameliorate Neurodevelopmental and Neurodegenerative Disorders

2022 ◽  
Vol 62 (1) ◽  
pp. 211-233
Author(s):  
Renata Bartesaghi ◽  
Stefano Vicari ◽  
William C. Mobley
Keyword(s):  
Down Syndrome ◽  
Neurodegenerative Disorders ◽  
Research Agenda ◽  
Behavioral Changes ◽  
Model Systems ◽  
Chromosome 21 ◽  
Rodent Models ◽  
Cell Models ◽  
Behavioral Challenges ◽  
And Behavior

Those with Down syndrome (DS)—trisomy for chromosome 21—are routinely impacted by cognitive dysfunction and behavioral challenges in children and adults and Alzheimer's disease in older adults. No proven treatments specifically address these cognitive or behavioral changes. However, advances in the establishment of rodent models and human cell models promise to support development of such treatments. A research agenda that emphasizes the identification of overexpressed genes that contribute demonstrably to abnormalities in cognition and behavior in model systems constitutes a rational next step. Normalizing expression of such genes may usher in an era of successful treatments applicable across the life span for those with DS.

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.

scholarly journals Building the Future Therapies for Down Syndrome: The Third International Conference of the T21 Research Society

2021 ◽  
pp. 1-17
Author(s):  
Mara Dierssen ◽  
Yann Herault ◽  
Pablo Helguera ◽  
Maria Martínez de Lagran ◽  
Anna Vazquez ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Trisomy 21 ◽  
Molecular Mechanisms ◽  
Scientific Organization ◽  
Research Society ◽  
Model Systems ◽  
Behavioral Challenges ◽  
International Conference ◽  
Cellular Processes ◽  
The Third

Research focused on Down syndrome has increased in the last several years to advance understanding of the consequences of trisomy 21 (T21) on molecular and cellular processes and, ultimately, on individuals with Down syndrome. The Trisomy 21 Research Society (T21RS) is the premier scientific organization for researchers and clinicians studying Down syndrome. The Third International Conference of T21RS, held June 6–9, 2019, in Barcelona, Spain, brought together 429 scientists, families, and industry representatives to share the latest discoveries on underlying cellular and molecular mechanisms of T21, define cognitive and behavioral challenges and better understand comorbidities associated with Down syndrome, including Alzheimer’s disease and leukemia. Presentation of cutting-edge results in neuroscience, neurology, model systems, psychology, cancer, biomarkers and molecular and phar­ma­cological therapeutic approaches demonstrate the compelling interest and continuing advancement in all aspects of understanding and ameliorating conditions associated with T21.

Cytogenetic, Molecular and FISH Analysis of an Isodicentric Chromosome 21 idic(21)(q22.3) in a Mildly-Affected Patient with Down Syndrome

2007 ◽  
Vol 7 (3) ◽  
pp. 215-218 ◽  
Author(s):  
Frenny J Sheth ◽  
Uppala Radhakrishna ◽  
Michael A Morris ◽  
Jean-Louis Blouin ◽  
Jayesh J Sheth ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Chromosome 21 ◽  
Fish Analysis ◽  
Affected Patient ◽  
Isodicentric Chromosome

scholarly journals A prenatal diagnosis case of partial duplication 21q21.1-q21.2 with normal phenotype maternally inherited

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Chunyan Jin ◽  
Zhiping Gu ◽  
Xiaohan Jiang ◽  
Pei Yu ◽  
Tianhui Xu
Keyword(s):  
Down Syndrome ◽  
Pregnant Woman ◽  
Prenatal Testing ◽  
Chromosome 21 ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Serological Screening ◽  
Partial Duplication ◽  
Her Family ◽  
Clinical Consequences

Abstract Background Down syndrome is characterized by trisomy 21 or partial duplication of chromosome 21. Extensive studies have focused on the identification of the Down Syndrome Critical Region (DSCR). We aim to provide evidence that duplication of 21q21.1-q21.2 should not be included in the DSCR and it has no clinical consequences on the phenotype. Case presentation Because serological screening was not performed at the appropriate gestational age, noninvasive prenatal testing (NIPT) analysis was performed for a pregnant woman with normal prenatal examinations at 22 weeks of gestation. The NIPT results revealed a 5.8 Mb maternally inherited duplication of 21q21.1-q21.2. To assess whether the fetus also carried this duplication, ultrasound-guided amniocentesis was conducted, and the result of chromosomal microarray analysis (CMA) with amniotic fluid showed a 6.7 Mb duplication of 21q21.1-q21.2 (ranging from position 18,981,715 to 25,707,009). This partial duplication of 21q21.1-q21.2 in the fetus was maternally inherited. After genetic counseling, the pregnant woman and her family decided to continue the pregnancy. Conclusion Our case clearly indicates that 21q21.1-q21.2 duplication is not included in the DSCR and most likely has no clinical consequences on phenotype.

scholarly journals Exploring Farmers’ Reasons for Antibiotic Use and Misuse in Pig Farms in Brazil

Antibiotics ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 331
Author(s):  
Rita Albernaz-Gonçalves ◽  
Gabriela Olmos ◽  
Maria José Hötzel
Keyword(s):  
Social Factors ◽  
Antibiotic Use ◽  
Behavioral Changes ◽  
Foreign Markets ◽  
Treatment Length ◽  
Key Stakeholders ◽  
Prevention And Treatment ◽  
Pig Farms ◽  
Unrestricted Access ◽  
And Behavior

Stressful management that makes farmed pigs susceptible to infections is associated with high antibiotic use (AMU) and resistance (AMR). Pig farmers are key stakeholders to support the international agenda pushing AMU restrictions. We interviewed 58 pig farmers on AMU/AMR, biosecurity, veterinary assistance, disease prevention and treatment, aiming to understand practices and attitudes towards the AMU/AMR problem. Farmers described a reliance on antibiotics to prevent and treat disease while neglecting biosecurity measures. We identified inappropriate AMU practices (high use of broad-spectrum antibiotics, incorrect dosage or treatment length) and unrestricted access to antibiotics, which encouraged imprudent AMU. Nevertheless, most farmers considered this AMU legitimate to guarantee herd productivity and showed unpreparedness and resistance to changing AMU practices, perceiving limitations (economic, sanitary and inspection) more easily than alternatives to reduce AMU. Agro-industries and foreign markets were mentioned, and internal consumers dismissed as potential motivators for behavioral changes. Importantly, farmers’ economic, technical and social factors may limit their autonomy to change practices. We conclude that the observed distancing of pig farmers from the AMU/AMR problem limits the efficiency of policies aiming for a prudent AMU. Our study indicates a need for education, training and behavior change nudging that should include other stakeholders beyond farmers.

scholarly journals Stress Responses in Down Syndrome Neurodegeneration: State of the Art and Therapeutic Molecules

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 266
Author(s):  
Chiara Lanzillotta ◽  
Fabio Di Domenico
Keyword(s):  
Down Syndrome ◽  
Stress Response ◽  
Stress Responses ◽  
Redox Balance ◽  
Antioxidant Response ◽  
Chromosome 21 ◽  
Therapeutic Approaches ◽  
Genomic Disorder ◽  
Therapeutic Molecules ◽  
Early Alzheimer’S Disease

Down syndrome (DS) is the most common genomic disorder characterized by the increased incidence of developing early Alzheimer’s disease (AD). In DS, the triplication of genes on chromosome 21 is intimately associated with the increase of AD pathological hallmarks and with the development of brain redox imbalance and aberrant proteostasis. Increasing evidence has recently shown that oxidative stress (OS), associated with mitochondrial dysfunction and with the failure of antioxidant responses (e.g., SOD1 and Nrf2), is an early signature of DS, promoting protein oxidation and the formation of toxic protein aggregates. In turn, systems involved in the surveillance of protein synthesis/folding/degradation mechanisms, such as the integrated stress response (ISR), the unfolded stress response (UPR), and autophagy, are impaired in DS, thus exacerbating brain damage. A number of pre-clinical and clinical studies have been applied to the context of DS with the aim of rescuing redox balance and proteostasis by boosting the antioxidant response and/or inducing the mechanisms of protein re-folding and clearance, and at final of reducing cognitive decline. So far, such therapeutic approaches demonstrated their efficacy in reverting several aspects of DS phenotype in murine models, however, additional studies aimed to translate these approaches in clinical practice are still needed.

scholarly journals PINK1 deficiency impairs adult neurogenesis of dopaminergic neurons

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sarah J. Brown ◽  
Ibrahim Boussaad ◽  
Javier Jarazo ◽  
Julia C. Fitzgerald ◽  
Paul Antony ◽  
...  
Keyword(s):  
Adult Neurogenesis ◽  
Neurodegenerative Disorders ◽  
Dopaminergic Neurons ◽  
Adult Life ◽  
Lineage Tracing ◽  
Model Systems ◽  
Wild Type ◽  
Therapeutic Approaches ◽  
Early Effect ◽  
Early Adult Life

AbstractRecent evidence suggests neurogenesis is on-going throughout life but the relevance of these findings for neurodegenerative disorders such as Parkinson’s disease (PD) is poorly understood. Biallelic PINK1 mutations cause early onset, Mendelian inherited PD. We studied the effect of PINK1 deficiency on adult neurogenesis of dopaminergic (DA) neurons in two complementary model systems. Zebrafish are a widely-used model to study neurogenesis in development and through adulthood. Using EdU analyses and lineage-tracing studies, we first demonstrate that a subset of ascending DA neurons and adjacent local-projecting DA neurons are each generated into adulthood in wild type zebrafish at a rate that decreases with age. Pink1-deficiency impedes DA neurogenesis in these populations, most significantly in early adult life. Pink1 already exerts an early effect on Th1+ progenitor cells rather than on differentiated DA neurons only. In addition, we investigate the effect of PINK1 deficiency in a human isogenic organoid model. Global neuronal differentiation in PINK1-deficient organoids and isogenic controls is similar, but PINK1-deficient organoids display impeded DA neurogenesis. The observation of impaired adult dopaminergic neurogenesis in Pink1 deficiency in two complementing model systems may have significant consequences for future therapeutic approaches in human PD patients with biallelic PINK1 mutations.

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