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Alliance"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:p>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<jats:italic>Dyrk1A<\/jats:italic>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 10<jats:sup>7<\/jats:sup>independent fragments identified 1,949 novel protein\u2013protein interactions. The direct interactors of HSA21 baits and rebounds were significantly enriched in ID-related genes (<jats:italic>P<\/jats:italic>-value &lt; 2.29 \u00d7 10<jats:sup>\u22128<\/jats:sup>). 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<jats:italic>Drosophila<\/jats:italic>and humans. The postsynaptic network was found to be enriched in proteins associated with ARC-related synaptic plasticity, ASD, and late-onset Alzheimer\u2019s disease. These results highlight links between DS and brain diseases with a complex genetic basis.<\/jats:p>","DOI":"10.26508\/lsa.202101205","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T20:15:11Z","timestamp":1659384911000},"page":"e202101205","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["Chr21 protein\u2013protein interactions: enrichment in proteins involved in intellectual disability, autism, and late-onset Alzheimer\u2019s disease"],"prefix":"10.26508","volume":"5","author":[{"given":"Julia","family":"Viard","sequence":"first","affiliation":[{"name":"Centre Psychiatrie and Neurosciences, INSERM U894, Paris, France"},{"name":"Laboratoire de G\u00e9nomique Fonctionnelle, CNG, Commissariat \u00e0 l\u2019\u00c9nergie Atomique et aux \u00c9nergies Alternatives (CEA), Evry, 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