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A pharmacological screen for compounds that rescue the developmental lethality of a Drosophila ATM mutant
Ataxia-telangiectasia (A-T) is a neurodegenerative disease caused by mutation of the A-T mutated (ATM) gene. ATM encodes a protein kinase that is activated by DNA damage and phosphorylates many proteins, including those involved in DNA repair, cell cycle control, and apoptosis. Characteristic biolog...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770031/ https://www.ncbi.nlm.nih.gov/pubmed/29338042 http://dx.doi.org/10.1371/journal.pone.0190821 |
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author | Rimkus, Stacey A. Wassarman, David A. |
author_facet | Rimkus, Stacey A. Wassarman, David A. |
author_sort | Rimkus, Stacey A. |
collection | PubMed |
description | Ataxia-telangiectasia (A-T) is a neurodegenerative disease caused by mutation of the A-T mutated (ATM) gene. ATM encodes a protein kinase that is activated by DNA damage and phosphorylates many proteins, including those involved in DNA repair, cell cycle control, and apoptosis. Characteristic biological and molecular functions of ATM observed in mammals are conserved in Drosophila melanogaster. As an example, conditional loss-of-function ATM alleles in flies cause progressive neurodegeneration through activation of the innate immune response. However, unlike in mammals, null alleles of ATM in flies cause lethality during development. With the goals of understanding biological and molecular roles of ATM in a whole animal and identifying candidate therapeutics for A-T, we performed a screen of 2400 compounds, including FDA-approved drugs, natural products, and bioactive compounds, for modifiers of the developmental lethality caused by a temperature-sensitive ATM allele (ATM(8)) that has reduced kinase activity at non-permissive temperatures. Ten compounds reproducibly suppressed the developmental lethality of ATM(8) flies, including Ronnel, which is an organophosphate. Ronnel and other suppressor compounds are known to cause mitochondrial dysfunction or to inhibit the enzyme acetylcholinesterase, which controls the levels of the neurotransmitter acetylcholine, suggesting that detrimental consequences of reduced ATM kinase activity can be rescued by inhibiting the function of mitochondria or increasing acetylcholine levels. We carried out further studies of Ronnel because, unlike the other compounds that suppressed the developmental lethality of homozygous ATM(8) flies, Ronnel was toxic to the development of heterozygous ATM(8) flies. Ronnel did not affect the innate immune response of ATM(8) flies, and it further increased the already high levels of DNA damage in brains of ATM(8) flies, but its effects were not harmful to the lifespan of rescued ATM(8) flies. These results provide new leads for understanding the biological and molecular roles of ATM and for the treatment of A-T. |
format | Online Article Text |
id | pubmed-5770031 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-57700312018-01-23 A pharmacological screen for compounds that rescue the developmental lethality of a Drosophila ATM mutant Rimkus, Stacey A. Wassarman, David A. PLoS One Research Article Ataxia-telangiectasia (A-T) is a neurodegenerative disease caused by mutation of the A-T mutated (ATM) gene. ATM encodes a protein kinase that is activated by DNA damage and phosphorylates many proteins, including those involved in DNA repair, cell cycle control, and apoptosis. Characteristic biological and molecular functions of ATM observed in mammals are conserved in Drosophila melanogaster. As an example, conditional loss-of-function ATM alleles in flies cause progressive neurodegeneration through activation of the innate immune response. However, unlike in mammals, null alleles of ATM in flies cause lethality during development. With the goals of understanding biological and molecular roles of ATM in a whole animal and identifying candidate therapeutics for A-T, we performed a screen of 2400 compounds, including FDA-approved drugs, natural products, and bioactive compounds, for modifiers of the developmental lethality caused by a temperature-sensitive ATM allele (ATM(8)) that has reduced kinase activity at non-permissive temperatures. Ten compounds reproducibly suppressed the developmental lethality of ATM(8) flies, including Ronnel, which is an organophosphate. Ronnel and other suppressor compounds are known to cause mitochondrial dysfunction or to inhibit the enzyme acetylcholinesterase, which controls the levels of the neurotransmitter acetylcholine, suggesting that detrimental consequences of reduced ATM kinase activity can be rescued by inhibiting the function of mitochondria or increasing acetylcholine levels. We carried out further studies of Ronnel because, unlike the other compounds that suppressed the developmental lethality of homozygous ATM(8) flies, Ronnel was toxic to the development of heterozygous ATM(8) flies. Ronnel did not affect the innate immune response of ATM(8) flies, and it further increased the already high levels of DNA damage in brains of ATM(8) flies, but its effects were not harmful to the lifespan of rescued ATM(8) flies. These results provide new leads for understanding the biological and molecular roles of ATM and for the treatment of A-T. Public Library of Science 2018-01-16 /pmc/articles/PMC5770031/ /pubmed/29338042 http://dx.doi.org/10.1371/journal.pone.0190821 Text en © 2018 Rimkus, Wassarman 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 use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Rimkus, Stacey A. Wassarman, David A. A pharmacological screen for compounds that rescue the developmental lethality of a Drosophila ATM mutant |
title | A pharmacological screen for compounds that rescue the developmental lethality of a Drosophila ATM mutant |
title_full | A pharmacological screen for compounds that rescue the developmental lethality of a Drosophila ATM mutant |
title_fullStr | A pharmacological screen for compounds that rescue the developmental lethality of a Drosophila ATM mutant |
title_full_unstemmed | A pharmacological screen for compounds that rescue the developmental lethality of a Drosophila ATM mutant |
title_short | A pharmacological screen for compounds that rescue the developmental lethality of a Drosophila ATM mutant |
title_sort | pharmacological screen for compounds that rescue the developmental lethality of a drosophila atm mutant |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770031/ https://www.ncbi.nlm.nih.gov/pubmed/29338042 http://dx.doi.org/10.1371/journal.pone.0190821 |
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