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Synapse diversity and synaptome architecture in human genetic disorders

Over 130 brain diseases are caused by mutations that disrupt genes encoding the proteome of excitatory synapses. These include neurological and psychiatric disorders with early and late onset such as autism, schizophrenia and depression and many other rarer conditions. The proteome of synapses is hi...

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Autor principal: Grant, Seth G N
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872429/
https://www.ncbi.nlm.nih.gov/pubmed/31348488
http://dx.doi.org/10.1093/hmg/ddz178
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author Grant, Seth G N
author_facet Grant, Seth G N
author_sort Grant, Seth G N
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description Over 130 brain diseases are caused by mutations that disrupt genes encoding the proteome of excitatory synapses. These include neurological and psychiatric disorders with early and late onset such as autism, schizophrenia and depression and many other rarer conditions. The proteome of synapses is highly complex with over 1000 conserved proteins which are differentially expressed generating a vast, potentially unlimited, number of synapse types. The diversity of synapses and their location in the brain are described by the synaptome. A recent study has mapped the synaptome across the mouse brain, revealing that synapse diversity is distributed into an anatomical architecture observed at scales from individual dendrites to the whole systems level. The synaptome architecture is built from the hierarchical expression and assembly of proteins into complexes and supercomplexes which are distributed into different synapses. Mutations in synapse proteins change the synaptome architecture leading to behavioral phenotypes. Mutations in the mechanisms regulating the hierarchical assembly of the synaptome, including transcription and proteostasis, may also change synapse diversity and synaptome architecture. The logic of synaptome hierarchical assembly provides a mechanistic framework that explains how diverse genetic disorders can converge on synapses in different brain circuits to produce behavioral phenotypes.
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spelling pubmed-68724292020-02-11 Synapse diversity and synaptome architecture in human genetic disorders Grant, Seth G N Hum Mol Genet Invited Review Article Over 130 brain diseases are caused by mutations that disrupt genes encoding the proteome of excitatory synapses. These include neurological and psychiatric disorders with early and late onset such as autism, schizophrenia and depression and many other rarer conditions. The proteome of synapses is highly complex with over 1000 conserved proteins which are differentially expressed generating a vast, potentially unlimited, number of synapse types. The diversity of synapses and their location in the brain are described by the synaptome. A recent study has mapped the synaptome across the mouse brain, revealing that synapse diversity is distributed into an anatomical architecture observed at scales from individual dendrites to the whole systems level. The synaptome architecture is built from the hierarchical expression and assembly of proteins into complexes and supercomplexes which are distributed into different synapses. Mutations in synapse proteins change the synaptome architecture leading to behavioral phenotypes. Mutations in the mechanisms regulating the hierarchical assembly of the synaptome, including transcription and proteostasis, may also change synapse diversity and synaptome architecture. The logic of synaptome hierarchical assembly provides a mechanistic framework that explains how diverse genetic disorders can converge on synapses in different brain circuits to produce behavioral phenotypes. Oxford University Press 2019-11-21 2019-07-26 /pmc/articles/PMC6872429/ /pubmed/31348488 http://dx.doi.org/10.1093/hmg/ddz178 Text en © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Invited Review Article
Grant, Seth G N
Synapse diversity and synaptome architecture in human genetic disorders
title Synapse diversity and synaptome architecture in human genetic disorders
title_full Synapse diversity and synaptome architecture in human genetic disorders
title_fullStr Synapse diversity and synaptome architecture in human genetic disorders
title_full_unstemmed Synapse diversity and synaptome architecture in human genetic disorders
title_short Synapse diversity and synaptome architecture in human genetic disorders
title_sort synapse diversity and synaptome architecture in human genetic disorders
topic Invited Review Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872429/
https://www.ncbi.nlm.nih.gov/pubmed/31348488
http://dx.doi.org/10.1093/hmg/ddz178
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