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Article ; Online: Network analysis of Down syndrome and SARS-CoV-2 identifies risk and protective factors for COVID-19.

De Toma, Ilario / Dierssen, Mara

2021 Volume 11, Issue 1, Page(s) 1930

Abstract: SARS-CoV-2 infection has spread uncontrollably worldwide while it remains unknown how vulnerable populations, such as Down syndrome (DS) individuals are affected by the COVID-19 pandemic. Individuals with DS have more risk of infections with respiratory ... ...

Abstract	SARS-CoV-2 infection has spread uncontrollably worldwide while it remains unknown how vulnerable populations, such as Down syndrome (DS) individuals are affected by the COVID-19 pandemic. Individuals with DS have more risk of infections with respiratory complications and present signs of auto-inflammation. They also present with multiple comorbidities that are associated with poorer COVID-19 prognosis in the general population. All this might place DS individuals at higher risk of SARS-CoV-2 infection or poorer clinical outcomes. In order to get insight into the interplay between DS genes and SARS-cov2 infection and pathogenesis we identified the genes associated with the molecular pathways involved in COVID-19 and the host proteins interacting with viral proteins from SARS-CoV-2. We then analyzed the overlaps of these genes with HSA21 genes, HSA21 interactors and other genes consistently differentially expressed in DS (using public transcriptomic datasets) and created a DS-SARS-CoV-2 network. We detected COVID-19 protective and risk factors among HSA21 genes and interactors and/or DS deregulated genes that might affect the susceptibility of individuals with DS both at the infection stage and in the progression to acute respiratory distress syndrome. Our analysis suggests that at the infection stage DS individuals might be more susceptible to infection due to triplication of TMPRSS2, that primes the viral S protein for entry in the host cells. However, as the anti-viral interferon I signaling is also upregulated in DS, this might increase the initial anti-viral response, inhibiting viral genome release, viral replication and viral assembly. In the second pro-inflammatory immunopathogenic phase of the infection, the prognosis for DS patients might worsen due to upregulation of inflammatory genes that might favor the typical cytokine storm of COVID-19. We also detected strong downregulation of the NLRP3 gene, critical for maintenance of homeostasis against pathogenic infections, possibly leading to bacterial infection complications.
MeSH term(s)	COVID-19/epidemiology ; COVID-19/genetics ; COVID-19/immunology ; COVID-19/metabolism ; Cytokine Release Syndrome/immunology ; Down Syndrome/epidemiology ; Down Syndrome/genetics ; Down Syndrome/immunology ; Down Syndrome/virology ; Gene Regulatory Networks ; Host Microbial Interactions ; Humans ; Inflammation/immunology ; Pandemics ; Protective Factors ; Risk Factors ; SARS-CoV-2/genetics ; SARS-CoV-2/isolation & purification ; Serine Endopeptidases/genetics ; Serine Endopeptidases/metabolism ; Transcriptome/genetics
Chemical Substances	Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS2 protein, human (EC 3.4.21.-)
Language	English
Publishing date	2021-01-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-81451-w
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Article ; Online: Network analysis of Down syndrome and SARS-CoV-2 identifies risk and protective factors for COVID-19

Ilario De Toma / Mara Dierssen

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 12

Abstract: Abstract SARS-CoV-2 infection has spread uncontrollably worldwide while it remains unknown how vulnerable populations, such as Down syndrome (DS) individuals are affected by the COVID-19 pandemic. Individuals with DS have more risk of infections with ... ...

Abstract	Abstract SARS-CoV-2 infection has spread uncontrollably worldwide while it remains unknown how vulnerable populations, such as Down syndrome (DS) individuals are affected by the COVID-19 pandemic. Individuals with DS have more risk of infections with respiratory complications and present signs of auto-inflammation. They also present with multiple comorbidities that are associated with poorer COVID-19 prognosis in the general population. All this might place DS individuals at higher risk of SARS-CoV-2 infection or poorer clinical outcomes. In order to get insight into the interplay between DS genes and SARS-cov2 infection and pathogenesis we identified the genes associated with the molecular pathways involved in COVID-19 and the host proteins interacting with viral proteins from SARS-CoV-2. We then analyzed the overlaps of these genes with HSA21 genes, HSA21 interactors and other genes consistently differentially expressed in DS (using public transcriptomic datasets) and created a DS-SARS-CoV-2 network. We detected COVID-19 protective and risk factors among HSA21 genes and interactors and/or DS deregulated genes that might affect the susceptibility of individuals with DS both at the infection stage and in the progression to acute respiratory distress syndrome. Our analysis suggests that at the infection stage DS individuals might be more susceptible to infection due to triplication of TMPRSS2, that primes the viral S protein for entry in the host cells. However, as the anti-viral interferon I signaling is also upregulated in DS, this might increase the initial anti-viral response, inhibiting viral genome release, viral replication and viral assembly. In the second pro-inflammatory immunopathogenic phase of the infection, the prognosis for DS patients might worsen due to upregulation of inflammatory genes that might favor the typical cytokine storm of COVID-19. We also detected strong downregulation of the NLRP3 gene, critical for maintenance of homeostasis against pathogenic infections, possibly leading to ...
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article ; Online: Meta-analysis of transcriptomic data reveals clusters of consistently deregulated gene and disease ontologies in Down syndrome.

De Toma, Ilario / Sierra, Cesar / Dierssen, Mara

PLoS computational biology

2021 Volume 17, Issue 9, Page(s) e1009317

Abstract: ... protein-protein interactions. We performed a meta-analysis integrating the differential expression (DE ...

Abstract	Trisomy of human chromosome 21 (HSA21) causes Down syndrome (DS). The trisomy does not simply result in the upregulation of HSA21--encoded genes but also leads to a genome-wide transcriptomic deregulation, which affect differently each tissue and cell type as a result of epigenetic mechanisms and protein-protein interactions. We performed a meta-analysis integrating the differential expression (DE) analyses of all publicly available transcriptomic datasets, both in human and mouse, comparing trisomic and euploid transcriptomes from different sources. We integrated all these data in a "DS network". We found that genome wide deregulation as a consequence of trisomy 21 is not arbitrary, but involves deregulation of specific molecular cascades in which both HSA21 genes and HSA21 interactors are more consistently deregulated compared to other genes. In fact, gene deregulation happens in "clusters", so that groups from 2 to 13 genes are found consistently deregulated. Most of these events of "co-deregulation" involve genes belonging to the same GO category, and genes associated with the same disease class. The most consistent changes are enriched in interferon related categories and neutrophil activation, reinforcing the concept that DS is an inflammatory disease. Our results also suggest that the impact of the trisomy might diverge in each tissue due to the different gene set deregulation, even though the triplicated genes are the same. Our original method to integrate transcriptomic data confirmed not only the importance of known genes, such as SOD1, but also detected new ones that could be extremely useful for generating or confirming hypotheses and supporting new putative therapeutic candidates. We created "metaDEA" an R package that uses our method to integrate every kind of transcriptomic data and therefore could be used with other complex disorders, such as cancer. We also created a user-friendly web application to query Ensembl gene IDs and retrieve all the information of their differential expression across the datasets.
MeSH term(s)	Animals ; Chromosomes, Human, Pair 21/genetics ; Computational Biology ; Databases, Genetic ; Disease Models, Animal ; Down Syndrome/genetics ; Gene Expression Profiling ; Gene Expression Regulation ; Gene Ontology ; Gene Regulatory Networks ; Humans ; Interferons/genetics ; Mice ; Neutrophil Activation/genetics ; Software
Chemical Substances	Interferons (9008-11-1)
Language	English
Publishing date	2021-09-27
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1009317
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Article ; Online: Meta-analysis of transcriptomic data reveals clusters of consistently deregulated gene and disease ontologies in Down syndrome.

Ilario De Toma / Cesar Sierra / Mara Dierssen

PLoS Computational Biology, Vol 17, Iss 9, p e

2021 Volume 1009317

Abstract: ... protein-protein interactions. We performed a meta-analysis integrating the differential expression (DE ...

Abstract	Trisomy of human chromosome 21 (HSA21) causes Down syndrome (DS). The trisomy does not simply result in the upregulation of HSA21--encoded genes but also leads to a genome-wide transcriptomic deregulation, which affect differently each tissue and cell type as a result of epigenetic mechanisms and protein-protein interactions. We performed a meta-analysis integrating the differential expression (DE) analyses of all publicly available transcriptomic datasets, both in human and mouse, comparing trisomic and euploid transcriptomes from different sources. We integrated all these data in a "DS network". We found that genome wide deregulation as a consequence of trisomy 21 is not arbitrary, but involves deregulation of specific molecular cascades in which both HSA21 genes and HSA21 interactors are more consistently deregulated compared to other genes. In fact, gene deregulation happens in "clusters", so that groups from 2 to 13 genes are found consistently deregulated. Most of these events of "co-deregulation" involve genes belonging to the same GO category, and genes associated with the same disease class. The most consistent changes are enriched in interferon related categories and neutrophil activation, reinforcing the concept that DS is an inflammatory disease. Our results also suggest that the impact of the trisomy might diverge in each tissue due to the different gene set deregulation, even though the triplicated genes are the same. Our original method to integrate transcriptomic data confirmed not only the importance of known genes, such as SOD1, but also detected new ones that could be extremely useful for generating or confirming hypotheses and supporting new putative therapeutic candidates. We created "metaDEA" an R package that uses our method to integrate every kind of transcriptomic data and therefore could be used with other complex disorders, such as cancer. We also created a user-friendly web application to query Ensembl gene IDs and retrieve all the information of their differential expression across ...
Keywords	Biology (General) ; QH301-705.5
Subject code	004
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article: Social Factors Influence Behavior in the Novel Object Recognition Task in a Mouse Model of Down Syndrome.

Sierra, Cesar / De Toma, Ilario / Cascio, Lorenzo Lo / Vegas, Esteban / Dierssen, Mara

Frontiers in behavioral neuroscience

2021 Volume 15, Page(s) 772734

Abstract: The use of mouse models has revolutionized the field of Down syndrome (DS), increasing our knowledge about neuropathology and helping to propose new therapies for cognitive impairment. However, concerns about the reproducibility of results in mice and ... ...

Abstract	The use of mouse models has revolutionized the field of Down syndrome (DS), increasing our knowledge about neuropathology and helping to propose new therapies for cognitive impairment. However, concerns about the reproducibility of results in mice and their translatability to humans have become a major issue, and controlling for moderators of behavior is essential. Social and environmental factors, the experience of the researcher, and the sex and strain of the animals can all have effects on behavior, and their impact on DS mouse models has not been explored. Here we analyzed the influence of a number of social and environmental factors, usually not taken into consideration, on the behavior of male and female wild-type and trisomic mice (the Ts65Dn model) in one of the most used tests for proving drug effects on memory, the novel object recognition (NOR) test. Using principal component analysis and correlation matrices, we show that the ratio of trisomic mice in the cage, the experience of the experimenter, and the timing of the test have a differential impact on male and female and on wild-type and trisomic behavior. We conclude that although the NOR test is quite robust and less susceptible to environmental influences than expected, to obtain useful results, the phenotype expression must be contrasted against the influences of social and environmental factors.
Language	English
Publishing date	2021-11-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452960-6
ISSN	1662-5153
ISSN	1662-5153
DOI	10.3389/fnbeh.2021.772734
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Article ; Online: Intensive assessment of executive functions derived from performance in cognitive training games.

Soldevila-Domenech, Natalia / De Toma, Ilario / Forcano, Laura / Diaz-Pellicer, Patrícia / Cuenca-Royo, Aida / Fagundo, Beatriz / Lorenzo, Thais / Gomis-Gonzalez, Maria / Sánchez-Benavides, Gonzalo / Fauria, Karine / Sastre, Carolina / Fernandez De Piérola, Íñigo / Molinuevo, José Luis / Verdejo-Garcia, Antonio / de la Torre, Rafael

iScience

2023 Volume 26, Issue 6, Page(s) 106886

Abstract: Traditional neuropsychological tests accurately describe the current cognitive state but fall short to characterize cognitive change over multiple short time periods. We present an innovative approach to remote monitoring of executive functions on a ... ...

Abstract	Traditional neuropsychological tests accurately describe the current cognitive state but fall short to characterize cognitive change over multiple short time periods. We present an innovative approach to remote monitoring of executive functions on a monthly basis, which leverages the performance indicators from self-administered computerized cognitive training games (NUP-EXE). We evaluated the measurement properties of NUP-EXE in N = 56 individuals (59% women, 60-80 years) at increased risk of Alzheimer's disease (
Language	English
Publishing date	2023-05-16
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.106886
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Article ; Online: Exploring the link between hedonic overeating and prefrontal cortex dysfunction in the Ts65Dn trisomic mouse model.

Fructuoso, Marta / Fernández-Blanco, Álvaro / Gallego-Román, Ana / Sierra, Cèsar / de Lagrán, María Martínez / Lorenzon, Nicola / De Toma, Ilario / Langohr, Klaus / Martín-García, Elena / Maldonado, Rafael / Dairou, Julien / Janel, Nathalie / Dierssen, Mara

Cellular and molecular life sciences : CMLS

2023 Volume 80, Issue 12, Page(s) 370

Abstract: Individuals with Down syndrome (DS) have a higher prevalence of obesity compared to the general population. Conventionally, this has been attributed to endocrine issues and lack of exercise. However, deficits in neural reward responses and dopaminergic ... ...

Abstract	Individuals with Down syndrome (DS) have a higher prevalence of obesity compared to the general population. Conventionally, this has been attributed to endocrine issues and lack of exercise. However, deficits in neural reward responses and dopaminergic disturbances in DS may be contributing factors. To investigate this, we focused on a mouse model (Ts65Dn) bearing some triplicated genes homologous to trisomy 21. Through detailed meal pattern analysis in male Ts65Dn mice, we observed an increased preference for energy-dense food, pointing towards a potential "hedonic" overeating behavior. Moreover, trisomic mice exhibited higher scores in compulsivity and inflexibility tests when limited access to energy-dense food and quinine hydrochloride adulteration were introduced, compared to euploid controls. Interestingly, when we activated prelimbic-to-nucleus accumbens projections in Ts65Dn male mice using a chemogenetic approach, impulsive and compulsive behaviors significantly decreased, shedding light on a promising intervention avenue. Our findings uncover a novel mechanism behind the vulnerability to overeating and offer potential new pathways for tackling obesity through innovative interventions.
MeSH term(s)	Humans ; Male ; Mice ; Animals ; Trisomy ; Down Syndrome/genetics ; Disease Models, Animal ; Prefrontal Cortex ; Hyperphagia/genetics ; Obesity/genetics
Language	English
Publishing date	2023-11-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-023-05009-x
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Article: A transcriptomic signature of X chromosome overdosage in Saudi Klinefelter syndrome induced pluripotent stem cells.

Astro, Veronica / Fiacco, Elisabetta / Cardona-Londoño, Kelly Johanna / De Toma, Ilario / Alzahrani, Hams Saeed / Alama, Jumana / Kokandi, Amal / Hamoda, Taha Abo-Almagd Abdel-Meguid / Felemban, Majed / Adamo, Antonio

Endocrine connections

2023 Volume 12, Issue 5

Abstract: Objective: The transcriptional landscape of Klinefelter syndromeduring early embryogenesis remains elusive. This study aimed to evaluate the impact of X chromosome overdosage in 47,XXY males induced pluripotent stem cells (iPSCs) obtained from patients ... ...

Abstract	Objective: The transcriptional landscape of Klinefelter syndromeduring early embryogenesis remains elusive. This study aimed to evaluate the impact of X chromosome overdosage in 47,XXY males induced pluripotent stem cells (iPSCs) obtained from patients with different genomic backgrounds and ethnicities. Design and method: We derived and characterized 15 iPSC lines from four Saudi 47,XXY KS patients and one Saudi 46,XY male. We performed a comparative transcriptional analysis using the Saudi KS-iPSCs and a cohort of European and North American KS-iPSCs. Results: We identified a panel of X-linked and autosomal genes commonly dysregulated in Saudi and European/North American KS-iPSCs vs 46,XY controls. Our findings demonstrate that seven PAR1 and nine non-PAR escape genes are consistently dysregulated and mostly display comparable transcriptional levels in both groups. Finally, we focused on genes commonly dysregulated in both iPSC cohorts and identified several gene-ontology categories highly relevant to KS physiopathology, including aberrant cardiac muscle contractility, skeletal muscle defects, abnormal synaptic transmission, and behavioral alterations. Conclusions: Our results indicate that a transcriptomic signature of X chromosome overdosage in KS is potentially attributable to a subset of X-linked genes sensitive to sex chromosome dosage and escaping X inactivation, regardless of the geographical area of origin, ethnicity, and genetic makeup.
Language	English
Publishing date	2023-04-26
Publishing country	England
Document type	Journal Article
ZDB-ID	2668428-7
ISSN	2049-3614
ISSN	2049-3614
DOI	10.1530/EC-22-0515
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Article ; Online: Transposable elements in brain health and disease.

Ahmadi, Amirhossein / De Toma, Ilario / Vilor-Tejedor, Natàlia / Eftekhariyan Ghamsari, Mohammad Reza / Sadeghi, Iman

Ageing research reviews

2020 Volume 64, Page(s) 101153

Abstract: Transposable elements (TEs) occupy a large fraction of the human genome but only a small proportion of these elements are still active today. Recent works have suggested that TEs are expressed and active in the brain, challenging the dogma that neuronal ... ...

Abstract	Transposable elements (TEs) occupy a large fraction of the human genome but only a small proportion of these elements are still active today. Recent works have suggested that TEs are expressed and active in the brain, challenging the dogma that neuronal genomes are static and revealing that they are susceptible to somatic genomic alterations. These new findings have major implications for understanding the neuroplasticity of the brain, which could hypothetically have a role in behavior and cognition, and contribute to vulnerability to disease. As active TEs could induce genetic diversity and mutagenesis, their influences on human brain development and diseases are of great interest. In this review, we will focus on the active TEs in the human genome and discuss in detail their impacts on human brain development. Furthermore, the association between TEs and brain-related diseases is discussed.
MeSH term(s)	Brain ; DNA Transposable Elements/genetics ; Genome, Human ; Genomics ; Humans
Chemical Substances	DNA Transposable Elements
Language	English
Publishing date	2020-09-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2075672-0
ISSN	1872-9649 ; 1568-1637
ISSN (online)	1872-9649
ISSN	1568-1637
DOI	10.1016/j.arr.2020.101153
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Article: DYRK1A Overexpression Alters Cognition and Neural-Related Proteomic Pathways in the Hippocampus That Are Rescued by Green Tea Extract and/or Environmental Enrichment.

De Toma, Ilario / Ortega, Mireia / Aloy, Patrick / Sabidó, Eduard / Dierssen, Mara

Frontiers in molecular neuroscience

2019 Volume 12, Page(s) 272

Abstract: Down syndrome (DS), caused by trisomy of chromosome 21, is the most common genetic cause of intellectual disability. We recently discovered that green tea extracts containing epigallocatechin-3-gallate (EGCG) improve cognition in mice transgenic ... ...

Abstract	Down syndrome (DS), caused by trisomy of chromosome 21, is the most common genetic cause of intellectual disability. We recently discovered that green tea extracts containing epigallocatechin-3-gallate (EGCG) improve cognition in mice transgenic for
Language	English
Publishing date	2019-11-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452967-9
ISSN	1662-5099
ISSN	1662-5099
DOI	10.3389/fnmol.2019.00272
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