Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain: Challenging the gene dosage effect hypothesis (Part II)

Cheon, Myeong Sook; Bajo, M.; Kim, S. H.; Claudio, Jaime O.; Stewart, A. Keith; Patterson, David; Kruger, Warren D.; Kondoh, Hisamoto; Lubec, Gert

doi:10.1007/s00726-002-0337-1

Cited by 32 publications

(9 citation statements)

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“…Triplication of Hsa21 genes in DS does not necessarily lead to a 1.5-fold increase (compared to euploid individuals) in their RNA or protein expression. For example, a study in DS fetal cortical tissue revealed multiple Hsa21 proteins in fact expressed at similar or lower levels than in disomic controls (Cheon et al, 2003a , b , c , d ). Assessments at transcriptomic and proteomic levels, together with meta-analysis across these studies, provide useful resources for understanding patterns of alteration in gene expression (for example, see Vilardell et al, 2011 ).…”

Section: Ds Models In the Study Of Candidate Genes Influencing Admentioning

confidence: 99%

Dissecting Alzheimer disease in Down syndrome using mouse models

Choong

Tosh

Pulford

et al. 2015

Front. Behav. Neurosci.

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Down syndrome (DS) is a common genetic condition caused by the presence of three copies of chromosome 21 (trisomy 21). This greatly increases the risk of Alzheimer disease (AD), but although virtually all people with DS have AD neuropathology by 40 years of age, not all develop dementia. To dissect the genetic contribution of trisomy 21 to DS phenotypes including those relevant to AD, a range of DS mouse models has been generated which are trisomic for chromosome segments syntenic to human chromosome 21. Here, we consider key characteristics of human AD in DS (AD-DS), and our current state of knowledge on related phenotypes in AD and DS mouse models. We go on to review important features needed in future models of AD-DS, to understand this type of dementia and so highlight pathogenic mechanisms relevant to all populations at risk of AD.

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Section: Ds Models In the Study Of Candidate Genes Influencing Admentioning

confidence: 99%

Dissecting Alzheimer disease in Down syndrome using mouse models

Choong

Tosh

Pulford

et al. 2015

Front. Behav. Neurosci.

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“…3 ). Prior studies have demonstrated increased expression of CBS in the brain of DS individuals; with high expression observed in astrocytes [ [14] , [15] , [16] , [17] ]. The current findings are consistent with these observations.…”

Section: Resultsmentioning

confidence: 99%

“…Due to a “gene dosage effect”, the elevation of CBS mRNA and CBS protein in individuals with DS has been well established for several decades [ [14] , [15] , [16] , [17] ]. Pierre Kamoun and his colleagues have demonstrated that DS individuals exhibit increased urinary levels of the stable H 2 S metabolite thiosulfate [ 21 , 22 ], a finding that has been also confirmed by an independent group [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Overproduction of hydrogen sulfide, generated by cystathionine β-synthase, disrupts brain wave patterns and contributes to neurobehavioral dysfunction in a rat model of down syndrome

et al. 2022

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“…Regarding its expression in the fetal DS brain, DYRK1A resulted as being overexpressed (RNA) at GW15–GW37 ( El Hajj et al, 2016 ) and GW20 ( Guimera et al, 1999 ), and DYRK1A protein was overexpressed at GW23 ( Park et al, 2010 ). However, no changes at the protein level were found at GW18–GW19 ( Cheon et al, 2003a ) or in infants aged 1–3 years, although DYRK1A was more widely expressed in DS adolescents and adults ( Dowjat et al, 2007 ). These discrepancies prompt further investigations.…”

Section: Genes Responsible For Neurogenesis Impairment In Down Syndromementioning

confidence: 95%

The Challenging Pathway of Treatment for Neurogenesis Impairment in Down Syndrome: Achievements and Perspectives

Stagni

Bartesaghi

2022

Front. Cell. Neurosci.

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Down syndrome (DS), also known as trisomy 21, is a genetic disorder caused by triplication of Chromosome 21. Gene triplication may compromise different body functions but invariably impairs intellectual abilities starting from infancy. Moreover, after the fourth decade of life people with DS are likely to develop Alzheimer’s disease. Neurogenesis impairment during fetal life stages and dendritic pathology emerging in early infancy are thought to be key determinants of alterations in brain functioning in DS. Although the progressive improvement in medical care has led to a notable increase in life expectancy for people with DS, there are currently no treatments for intellectual disability. Increasing evidence in mouse models of DS reveals that pharmacological interventions in the embryonic and neonatal periods may greatly benefit brain development and cognitive performance. The most striking results have been obtained with pharmacotherapies during embryonic life stages, indicating that it is possible to pharmacologically rescue the severe neurodevelopmental defects linked to the trisomic condition. These findings provide hope that similar benefits may be possible for people with DS. This review summarizes current knowledge regarding (i) the scope and timeline of neurogenesis (and dendritic) alterations in DS, in order to delineate suitable windows for treatment; (ii) the role of triplicated genes that are most likely to be the key determinants of these alterations, in order to highlight possible therapeutic targets; and (iii) prenatal and neonatal treatments that have proved to be effective in mouse models, in order to rationalize the choice of treatment for human application. Based on this body of evidence we will discuss prospects and challenges for fetal therapy in individuals with DS as a potential means of drastically counteracting the deleterious effects of gene triplication.

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Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain: Challenging the gene dosage effect hypothesis (Part II)

Cited by 32 publications

References 0 publications

Dissecting Alzheimer disease in Down syndrome using mouse models

Dissecting Alzheimer disease in Down syndrome using mouse models

Overproduction of hydrogen sulfide, generated by cystathionine β-synthase, disrupts brain wave patterns and contributes to neurobehavioral dysfunction in a rat model of down syndrome

The Challenging Pathway of Treatment for Neurogenesis Impairment in Down Syndrome: Achievements and Perspectives

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