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Updated: Feb 15, 2026
High-Throughput Robotically Assisted Isolation of Temperature-sensitive Lethal Mutants in Chlamydomonas reinhardtii
Published on: December 5, 2016
A pharmacological screen for compounds that rescue the developmental lethality of a Drosophila ATM mutant
Stacey A Rimkus1, David A Wassarman1
1Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI.
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.
Insights
This study screened compounds to find treatments for Ataxia-telangiectasia (A-T), a neurodegenerative disease. Ronnel and other compounds suppressed developmental lethality in ATM gene-mutant flies, offering potential A-T therapeutic leads.
Area of Science:
- Genetics
- Neuroscience
- Pharmacology
Background:
- Ataxia-telangiectasia (A-T) is a neurodegenerative disorder linked to mutations in the ATM gene.
- ATM protein kinase is crucial for DNA damage response, cell cycle control, and apoptosis.
- ATM functions are conserved in Drosophila melanogaster, where ATM loss-of-function causes neurodegeneration.
Purpose of the Study:
- To understand the biological and molecular roles of ATM in a whole organism.
- To identify potential therapeutic compounds for A-T by screening for modifiers of ATM-related developmental lethality.
Main Methods:
- A large-scale screen of 2400 compounds was conducted using a temperature-sensitive ATM allele (ATM8) in Drosophila.
- Compounds were tested for their ability to suppress the developmental lethality of ATM8 flies.
- Further studies investigated the effects of the suppressor compound Ronnel on ATM8 flies.
Main Results:
- Ten compounds, including the organophosphate Ronnel, reproducibly suppressed the developmental lethality of ATM8 flies.
- Suppressor compounds suggest that mitochondrial dysfunction or increased acetylcholine levels may rescue ATM deficiency.
- Ronnel exacerbated DNA damage but did not harm the lifespan of rescued flies, despite toxicity in heterozygous flies.
Conclusions:
- This study identified novel compounds, including Ronnel, that mitigate developmental defects associated with ATM mutations.
- Findings suggest potential therapeutic strategies for A-T involving mitochondrial function or acetylcholine pathways.
- The results provide new insights into ATM's biological roles and potential A-T treatments.
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