dc.contributor.author
Viard, Julia
dc.contributor.author
Loe-Mie, Yann
dc.contributor.author
Daudin, Rachel
dc.contributor.author
Khelfaoui, Malik
dc.contributor.author
Plancon, Christine
dc.contributor.author
Boland, Anne
dc.contributor.author
Tejedor, Francisco
dc.contributor.author
Huganir, Richard L.
dc.contributor.author
Kim, Eunjoon
dc.contributor.author
Haucke, Volker
dc.date.accessioned
2022-09-20T11:40:27Z
dc.date.available
2022-09-20T11:40:27Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/36392
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-36108
dc.description.abstract
Down syndrome (DS) is caused by human chromosome 21 (HSA21) trisomy. It is characterized by a poorly understood intellectual disability (ID). We studied two mouse models of DS, one with an extra copy of the Dyrk1A gene (189N3) and the other with an extra copy of the mouse Chr16 syntenic region (Dp(16)1Yey). RNA-seq analysis of the transcripts deregulated in the embryonic hippocampus revealed an enrichment in genes associated with chromatin for the 189N3 model, and synapses for the Dp(16)1Yey model. A large-scale yeast two-hybrid screen (82 different screens, including 72 HSA21 baits and 10 rebounds) of a human brain library containing at least 107 independent fragments identified 1,949 novel protein–protein interactions. The direct interactors of HSA21 baits and rebounds were significantly enriched in ID-related genes (P-value < 2.29 × 10−8). Proximity ligation assays showed that some of the proteins encoded by HSA21 were located at the dendritic spine postsynaptic density, in a protein network at the dendritic spine postsynapse. We located HSA21 DYRK1A and DSCAM, mutations of which increase the risk of autism spectrum disorder (ASD) 20-fold, in this postsynaptic network. We found that an intracellular domain of DSCAM bound either DLGs, which are multimeric scaffolds comprising receptors, ion channels and associated signaling proteins, or DYRK1A. The DYRK1A-DSCAM interaction domain is conserved in Drosophila and humans. The postsynaptic network was found to be enriched in proteins associated with ARC-related synaptic plasticity, ASD, and late-onset Alzheimer’s disease. These results highlight links between DS and brain diseases with a complex genetic basis.
en
dc.format.extent
17 Seiten
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
protein interactions
en
dc.subject.ddc
500 Naturwissenschaften und Mathematik::570 Biowissenschaften; Biologie::570 Biowissenschaften; Biologie
dc.title
Chr21 protein–protein interactions: enrichment in proteins involved in intellectual disability, autism, and late-onset Alzheimer’s disease
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
e202101205
dcterms.bibliographicCitation.doi
10.26508/lsa.202101205
dcterms.bibliographicCitation.journaltitle
Life Science Alliance
dcterms.bibliographicCitation.number
12
dcterms.bibliographicCitation.volume
5
dcterms.bibliographicCitation.url
https://doi.org/10.26508/lsa.202101205
refubium.affiliation
Biologie, Chemie, Pharmazie
refubium.affiliation.other
Institut für Chemie und Biochemie
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refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.isPartOf.eissn
2575-1077
refubium.resourceType.provider
WoS-Alert