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Kim, Eunjoon
시냅스 뇌질환 연구단
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Chr21 protein-protein interactions: enrichment in proteins involved in intellectual disability, autism, and late-onset Alzheimer's disease

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Title
Chr21 protein-protein interactions: enrichment in proteins involved in intellectual disability, autism, and late-onset Alzheimer's disease
Author(s)
Viard, Julia; Loe-Mie, Yann; Daudin, Rachel; Khelfaoui, Malik; Plancon, Christine; Boland, Anne; Tejedor, Francisco; Huganir, Richard L.; Eunjoon Kim; Kinoshita, Makoto; Liu, Guofa; Haucke, Volker; Moncion, Thomas; Yu, Eugene; Hindie, Valerie; Blehaut, Henri; Mircher, Clotilde; Herault, Yann; Deleuze, Jean-Francois; Rain, Jean-Christophe; Simonneau, Michel; Lepagnol-Bestel, Aude-Marie
Publication Date
2022-12
Journal
LIFE SCIENCE ALLIANCE, v.5, no.12
Publisher
LIFE SCIENCE ALLIANCE LLC
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 x 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.
URI
https://pr.ibs.re.kr/handle/8788114/12370
DOI
10.26508/lsa.202101205
ISSN
2575-1077
Appears in Collections:
Center for Synaptic Brain Dysfunctions(시냅스 뇌질환 연구단) > 1. Journal Papers (저널논문)
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