Altered reactivity to threatening stimuli in Drosophila models of Parkinson's disease, revealed by a trial-based assay

Kajtor, Márton and Billes, Viktor András and Király, Bálint and Karkusova, Patricia and Kovács, Tibor and Stabb, Hannah and Tóthné Sviatkó, Katalin and Vizi, Andor and Ujvari, Eszter and Balázsfi, Diána and Seidenbecher, Sophie E. and Kvitsiani, Duda and Vellai, Tibor and Hangya, Balázs (2025) Altered reactivity to threatening stimuli in Drosophila models of Parkinson's disease, revealed by a trial-based assay. ELIFE, 13. ISSN 2050-084X

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Abstract

The fruit fly Drosophila melanogaster emerges as an affordable, genetically tractable model of behavior and brain diseases. However, despite the surprising level of evolutionary conservation from flies to humans, significant genetic, circuit-level, and behavioral differences hinder the interpretability of fruit fly models for human disease. Therefore, to allow a more direct fly-versus-human comparison, we surveyed the rarely exploited, rich behavioral repertoire of fruit flies with genetic alterations relevant to Parkinson's disease (PD), including overexpression of human mutant Parkin or alpha-synuclein proteins and mutations in dopamine receptors. Flies with different genetic backgrounds displayed variable behaviors, including freezing, slowing, and running, in response to predator-mimicking passing shadows used as threatening stimuli in a single-animal trial-based assay. We found that the expression of human mutant Parkin in flies resulted in reduced walking speed and decreased reactivity to passing shadows. Flies with dopamine receptor mutations showed similar alterations, consistent with the motor and cognitive deficits typical in humans with PD. We also found age-dependent trends in behavioral choice during the fly lifespan, while dopamine receptor mutant flies maintained their decreased general reactivity throughout all age groups. Our data demonstrate that single-trial behavioral analysis can reveal subtle behavioral changes in mutant flies that can be used to further our understanding of disease pathomechanisms and help gauge the validity of genetic Drosophila models of neurodegeneration, taking us one step closer to bridging the gap in fly-to-human translation.

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