A synaptic molecular dependency network in knockdown of autism- and schizophrenia-associated genes revealed by multiplexed imaging.
Bayesian network inference
CP: Genomics
CP: Neuroscience
RNAi
autism
genetic screen
molecular network
multiplexed imaging
schizophrenia
siRNA
synapse
synaptic protein
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
30 05 2023
30 05 2023
Historique:
received:
24
08
2022
revised:
29
01
2023
accepted:
08
04
2023
medline:
5
6
2023
pubmed:
26
4
2023
entrez:
26
4
2023
Statut:
ppublish
Résumé
The complex functions of neuronal synapses depend on their tightly interconnected protein network, and their dysregulation is implicated in the pathogenesis of autism spectrum disorders and schizophrenia. However, it remains unclear how synaptic molecular networks are altered biochemically in these disorders. Here, we apply multiplexed imaging to probe the effects of RNAi knockdown of 16 autism- and schizophrenia-associated genes on the simultaneous joint distribution of 10 synaptic proteins, observing several protein composition phenotypes associated with these risk genes. We apply Bayesian network analysis to infer hierarchical dependencies among eight excitatory synaptic proteins, yielding predictive relationships that can only be accessed with single-synapse, multiprotein measurements performed simultaneously in situ. Finally, we find that central features of the network are affected similarly across several distinct gene knockdowns. These results offer insight into the convergent molecular etiology of these widespread disorders and provide a general framework to probe subcellular molecular networks.
Identifiants
pubmed: 37099425
pii: S2211-1247(23)00441-2
doi: 10.1016/j.celrep.2023.112430
pmc: PMC10259678
mid: NIHMS1903745
pii:
doi:
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
112430Subventions
Organisme : NIMH NIH HHS
ID : R01 MH112694
Pays : United States
Organisme : NIMH NIH HHS
ID : R21 MH130624
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES002109
Pays : United States
Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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