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Updated: Jun 2, 2026
Behavioral Analysis of Locomotor Dysfunction in Drosophila melanogaster as a Readout for Neurotoxicity
Published on: July 18, 2025
Drosophila melanogaster: a new model to study cisplatin-induced neurotoxicity
Jewel L Podratz1, Nathan P Staff, Dara Froemel
1Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA.
Abstract:
Platinum-based compounds are widely used and effective chemotherapeutic agents; however, sensory peripheral neuropathy is a dose-limiting and long term side effect for 20-30% of patients. A critical question is whether the mechanisms of cell death underlying clinical efficacy can be separated from the effects on neurons in order to develop strategies that prevent platinum-induced neuropathy. In rodent dorsal root ganglion neurons (DRG), cisplatin has been shown to bind and damage neuronal DNA, inducing apoptosis; however genetic manipulation in order to study mechanisms of this phenomenon in the rodent model system is costly and time-consuming. Drosophila melanogaster are commonly used to study neurological disorders, have DNA damage-apoptosis mechanisms homologous to mammalian systems, and have readily-available, inexpensive tools for rapid genetic manipulation. We therefore sought to develop adult Drosophila as a new model to study cisplatin-induced neurotoxicity. Adult Drosophila were exposed to 10, 25, 50, 100, 200 and 400 microg/ml cisplatin for 3 days and observed for fly survival and geotactic climbing behavior, cisplatin-DNA binding and cellular apoptosis. On day 3, 50 microg/ml cisplatin reduced the number of flies able to climb above 2 cm to 43% while fly survival was maintained at 92%. 100% lethality was observed at 400 microg/ml cisplatin. Whole fly platinum-genomic DNA adducts were measured and found to be comparable to adduct levels previously measured in rat DRG neurons. Brain, ovaries, kidney and heart harvested from cisplatin treated flies were stained for active caspase 3. Apoptosis was found in ovaries and brain but not in heart and kidney. Brain apoptosis was confirmed by transmission electron microscopy. Expression of the anti-apoptotic baculoviral protein, p35, in neurons using the GAL4-UAS system prevented cisplatin-induced apoptosis in the brain and restored climbing behavior. In conclusion, cisplatin-induced behavioral and apoptotic changes in Drosophila resemble those seen in mammals. Furthermore, the use of lethality and climbing assays combined with powerful gene manipulation, make Drosophila a suitable model to study mechanisms of cisplatin neurotoxicity.
Insights
Fruit flies offer a new, rapid model for studying chemotherapy side effects. Researchers found that cisplatin causes neurotoxicity and apoptosis in flies, similar to mammals, enabling faster research into preventing nerve damage.
Area of Science:
- Neuroscience
- Toxicology
- Genetics
Background:
- Platinum-based chemotherapy is effective but causes dose-limiting neurotoxicity.
- Understanding platinum-induced neuropathy mechanisms is crucial for developing preventative strategies.
- Rodent models for studying neurotoxicity are costly and time-consuming.
Purpose of the Study:
- To establish adult Drosophila as a novel, rapid model for investigating cisplatin-induced neurotoxicity.
- To compare cisplatin's effects on fly neurons with those observed in mammalian systems.
Main Methods:
- Adult Drosophila were exposed to varying cisplatin concentrations.
- Assessed fly survival, geotactic climbing behavior, DNA-adduct formation, and apoptosis (active caspase 3 staining).
- Utilized the GAL4-UAS system to express the anti-apoptotic protein p35 in neurons.
Main Results:
- Cisplatin induced dose-dependent lethality and impaired climbing behavior.
- Platinum-DNA adducts in flies were comparable to rodent models.
- Apoptosis was observed in fly brains and ovaries, but not heart or kidney.
- Neuronal expression of p35 prevented cisplatin-induced brain apoptosis and restored climbing.
Conclusions:
- Adult Drosophila effectively model cisplatin-induced neurotoxicity, mirroring mammalian responses.
- The fly model, combined with genetic tools, facilitates rapid mechanistic studies of neurotoxicity.
- This model system holds promise for developing strategies to prevent chemotherapy-induced peripheral neuropathy.
