Molecular convergence between Down syndrome and fragile X syndrome identified using human pluripotent stem cell models

Susco, Sara G.; Ghosh, Sulagna; Mazzucato, Patrizia; Angelini, Gabriella; Beccard, Amanda; Barrera, Víctor; Berryer, Martin H.; Messana, Angelica; Lam, Daisy; Hazelbaker, Dane Z.; Barrett, Lindy E.

doi:10.1016/j.celrep.2022.111312

Cited by 5 publications

(2 citation statements)

References 103 publications

(157 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…FMR encodes the Fragile X mental retardation protein (FMRP), which binds to its target mRNAs to repress their translation [ 90 , 91 ]. FMRP targets include the mRNAs of several HSA21 genes, including DSCAM, DYRK1A, NCAM2, and APP [ 92 ]. Like DS patients, FXS patients exhibit increased expression of DSCAM, DYRK1A, NCAM2, and APP.…”

Section: The Contribution Of Dscam To the Pathogenesis Of Ds And Asso...mentioning

confidence: 99%

See 1 more Smart Citation

The role of Down syndrome cell adhesion molecule in Down syndrome

Hergenreder,

Yang,

2024

Medical Review

View full text Add to dashboard Cite

Down syndrome (DS) is caused by the presence of an extra copy of the entire or a portion of human chromosome 21 (HSA21). This genomic alteration leads to elevated expression of numerous HSA21 genes, resulting in a variety of health issues in individuals with DS. Among the genes located in the DS “critical region” of HSA21, Down syndrome cell adhesion molecule (DSCAM) plays an important role in neuronal development. There is a growing body of evidence underscoring DSCAM’s involvement in various DS-related disorders. This review aims to provide a concise overview of the established functions of DSCAM, with a particular focus on its implications in DS. We delve into the roles that DSCAM plays in DS-associated diseases. In the concluding section of this review, we explore prospective avenues for future research to further unravel DSCAM’s role in DS and opportunities for therapeutic treatments.

show abstract

Section: The Contribution Of Dscam To the Pathogenesis Of Ds And Asso...mentioning

confidence: 99%

“…Like DS patients, FXS patients exhibit increased expression of DSCAM, DYRK1A, NCAM2, and APP. In DS patient-derived pluripotent stem cell models, an acute increase in FMRP reduces the expression levels of DS-related proteins and reverses 40 % of global transcriptional changes [ 92 ].…”

Section: The Contribution Of Dscam To the Pathogenesis Of Ds And Asso...mentioning

confidence: 99%

The role of Down syndrome cell adhesion molecule in Down syndrome

Hergenreder,

Yang,

2024

Medical Review

View full text Add to dashboard Cite

show abstract

Neurobehavioral dysfunction in a mouse model of Down syndrome: upregulation of cystathionine β-synthase, H2S overproduction, altered protein persulfidation, synaptic dysfunction, endoplasmic reticulum stress, and autophagy

Panagaki,

Janickova,

Petrovic

et al. 2024

GeroScience

View full text Add to dashboard Cite

Down syndrome (DS) is a genetic condition where the person is born with an extra chromosome 21. DS is associated with accelerated aging; people with DS are prone to age-related neurological conditions including an early-onset Alzheimer’s disease. Using the Dp(17)3Yey/ + mice, which overexpresses a portion of mouse chromosome 17, which encodes for the transsulfuration enzyme cystathionine β-synthase (CBS), we investigated the functional role of the CBS/hydrogen sulfide (H2S) pathway in the pathogenesis of neurobehavioral dysfunction in DS. The data demonstrate that CBS is higher in the brain of the DS mice than in the brain of wild-type mice, with primary localization in astrocytes. DS mice exhibited impaired recognition memory and spatial learning, loss of synaptosomal function, endoplasmic reticulum stress, and autophagy. Treatment of mice with aminooxyacetate, a prototypical CBS inhibitor, improved neurobehavioral function, reduced the degree of reactive gliosis in the DS brain, increased the ability of the synaptosomes to generate ATP, and reduced endoplasmic reticulum stress. H2S levels in the brain of DS mice were higher than in wild-type mice, but, unexpectedly, protein persulfidation was decreased. Many of the above alterations were more pronounced in the female DS mice. There was a significant dysregulation of metabolism in the brain of DS mice, which affected amino acid, carbohydrate, lipid, endocannabinoid, and nucleotide metabolites; some of these alterations were reversed by treatment of the mice with the CBS inhibitor. Thus, the CBS/H2S pathway contributes to the pathogenesis of neurological dysfunction in DS in the current animal model.

show abstract