1. A pharmacological screen for compounds that rescue the developmental lethality of a Drosophila ATM mutant
- Author
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David A. Wassarman and Stacey A. Rimkus
- Subjects
0301 basic medicine ,Male ,Mutant ,Drug Evaluation, Preclinical ,Electrophoretic techniques ,DNA electrophoresis ,Genes, Insect ,Ataxia Telangiectasia Mutated Proteins ,medicine.disease_cause ,Biochemistry ,0302 clinical medicine ,Medicine and Health Sciences ,Drosophila Proteins ,Brain Damage ,Immune Response ,Energy-Producing Organelles ,Mutation ,Multidisciplinary ,biology ,Drosophila Melanogaster ,Eukaryota ,Animal Models ,Null allele ,Cell biology ,Mitochondria ,Nucleic acids ,Insects ,Phenotype ,Neurology ,Experimental Organism Systems ,Medicine ,Female ,Drosophila ,Drosophila melanogaster ,Cellular Structures and Organelles ,Research Article ,Arthropoda ,DNA repair ,DNA damage ,Science ,Immunology ,Library Screening ,Protein Serine-Threonine Kinases ,Bioenergetics ,Research and Analysis Methods ,03 medical and health sciences ,Model Organisms ,medicine ,Genetics ,Animals ,Kinase activity ,Molecular Biology Techniques ,Molecular Biology ,Alleles ,Molecular Biology Assays and Analysis Techniques ,Innate immune system ,Biology and life sciences ,fungi ,Organisms ,Organothiophosphorus Compounds ,DNA ,Cell Biology ,biology.organism_classification ,Invertebrates ,Immunity, Innate ,030104 developmental biology ,Nerve Degeneration ,Genes, Lethal ,030217 neurology & neurosurgery - Abstract
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 (ATM8) that has reduced kinase activity at non-permissive temperatures. Ten compounds reproducibly suppressed the developmental lethality of ATM8 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 ATM8 flies, Ronnel was toxic to the development of heterozygous ATM8 flies. Ronnel did not affect the innate immune response of ATM8 flies, and it further increased the already high levels of DNA damage in brains of ATM8 flies, but its effects were not harmful to the lifespan of rescued ATM8 flies. These results provide new leads for understanding the biological and molecular roles of ATM and for the treatment of A-T.
- Published
- 2017