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Genome-wide analysis reveals novel regulators of synaptic maintenance in Drosophila

Maintaining synaptic communication is required to preserve nervous system function as an organism ages. While much work has been accomplished to understand synapse formation and development, we understand relatively little regarding maintaining synaptic integrity throughout aging. To better understa...

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Autores principales: Sidisky, Jessica M, de Paula Moreira, Danielle, Okumus, Meryem, Caratenuto, Russell, Drost, Cassidy, Connors, Bali, Hussain, Sarrah, Alkhatib, Stephanie, Babcock, Daniel T
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10078915/
https://www.ncbi.nlm.nih.gov/pubmed/36799927
http://dx.doi.org/10.1093/genetics/iyad025
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author Sidisky, Jessica M
de Paula Moreira, Danielle
Okumus, Meryem
Caratenuto, Russell
Drost, Cassidy
Connors, Bali
Hussain, Sarrah
Alkhatib, Stephanie
Babcock, Daniel T
author_facet Sidisky, Jessica M
de Paula Moreira, Danielle
Okumus, Meryem
Caratenuto, Russell
Drost, Cassidy
Connors, Bali
Hussain, Sarrah
Alkhatib, Stephanie
Babcock, Daniel T
author_sort Sidisky, Jessica M
collection PubMed
description Maintaining synaptic communication is required to preserve nervous system function as an organism ages. While much work has been accomplished to understand synapse formation and development, we understand relatively little regarding maintaining synaptic integrity throughout aging. To better understand the mechanisms responsible for maintaining synaptic structure and function, we performed an unbiased forward genetic screen to identify genes required for synapse maintenance of adult Drosophila neuromuscular junctions. Using flight behavior as a screening tool, we evaluated flight ability in 198 lines from the Drosophila Genetic Reference Panel to identify single nucleotide polymorphisms (SNPs) that are associated with a progressive loss of flight ability with age. Among the many candidate genes identified from this screen, we focus here on 10 genes with clear human homologs harboring SNPs that are most highly associated with synaptic maintenance. Functional validation of these genes using mutant alleles revealed a progressive loss of synaptic structural integrity. Tissue-specific knockdown of these genes using RNA interference (RNAi) uncovered important roles for these genes in either presynaptic motor neurons, postsynaptic muscles, or associated glial cells, highlighting the importance of each component of tripartite synapses. These results offer greater insight into the mechanisms responsible for maintaining structural and functional integrity of synapses with age.
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spelling pubmed-100789152023-04-07 Genome-wide analysis reveals novel regulators of synaptic maintenance in Drosophila Sidisky, Jessica M de Paula Moreira, Danielle Okumus, Meryem Caratenuto, Russell Drost, Cassidy Connors, Bali Hussain, Sarrah Alkhatib, Stephanie Babcock, Daniel T Genetics Investigation Maintaining synaptic communication is required to preserve nervous system function as an organism ages. While much work has been accomplished to understand synapse formation and development, we understand relatively little regarding maintaining synaptic integrity throughout aging. To better understand the mechanisms responsible for maintaining synaptic structure and function, we performed an unbiased forward genetic screen to identify genes required for synapse maintenance of adult Drosophila neuromuscular junctions. Using flight behavior as a screening tool, we evaluated flight ability in 198 lines from the Drosophila Genetic Reference Panel to identify single nucleotide polymorphisms (SNPs) that are associated with a progressive loss of flight ability with age. Among the many candidate genes identified from this screen, we focus here on 10 genes with clear human homologs harboring SNPs that are most highly associated with synaptic maintenance. Functional validation of these genes using mutant alleles revealed a progressive loss of synaptic structural integrity. Tissue-specific knockdown of these genes using RNA interference (RNAi) uncovered important roles for these genes in either presynaptic motor neurons, postsynaptic muscles, or associated glial cells, highlighting the importance of each component of tripartite synapses. These results offer greater insight into the mechanisms responsible for maintaining structural and functional integrity of synapses with age. Oxford University Press 2023-02-17 /pmc/articles/PMC10078915/ /pubmed/36799927 http://dx.doi.org/10.1093/genetics/iyad025 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Genetics Society of America. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Investigation
Sidisky, Jessica M
de Paula Moreira, Danielle
Okumus, Meryem
Caratenuto, Russell
Drost, Cassidy
Connors, Bali
Hussain, Sarrah
Alkhatib, Stephanie
Babcock, Daniel T
Genome-wide analysis reveals novel regulators of synaptic maintenance in Drosophila
title Genome-wide analysis reveals novel regulators of synaptic maintenance in Drosophila
title_full Genome-wide analysis reveals novel regulators of synaptic maintenance in Drosophila
title_fullStr Genome-wide analysis reveals novel regulators of synaptic maintenance in Drosophila
title_full_unstemmed Genome-wide analysis reveals novel regulators of synaptic maintenance in Drosophila
title_short Genome-wide analysis reveals novel regulators of synaptic maintenance in Drosophila
title_sort genome-wide analysis reveals novel regulators of synaptic maintenance in drosophila
topic Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10078915/
https://www.ncbi.nlm.nih.gov/pubmed/36799927
http://dx.doi.org/10.1093/genetics/iyad025
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