Kajtor Márton, Billes Viktor András, Király Bálint, Karkusova Patricia, Kovács Tibor, Stabb Hannah, Sviatkó Katalin, Vizi Andor, Ujvári Eszter, Balázsfi Diána, Seidenbecher Sophie E, Kvitsiani Duda, Vellai Tibor, Hangya Balázs
MTA-HUN-REN KOKI Lendület "Momentum" Laboratory of Systems Neuroscience, Institute of Experimental Medicine, Budapest, Hungary.
Department of Genetics, Eötvös Loránd University, Budapest, Hungary.
Elife. 2025 Jul 29;13:RP90905. doi: 10.7554/eLife.90905.
The fruit fly 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 α-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 models of neurodegeneration, taking us one step closer to bridging the gap in fly-to-human translation.
果蝇成为一种经济实惠、在遗传学上易于处理的行为和脑部疾病模型。然而，尽管从果蝇到人类在进化上具有惊人的保守程度，但显著的基因、神经回路水平和行为差异阻碍了果蝇模型对人类疾病的解释力。因此，为了进行更直接的果蝇与人类的比较，我们调查了果蝇鲜少被研究的丰富行为库，这些果蝇具有与帕金森病（PD）相关的基因改变，包括人类突变型帕金蛋白或α-突触核蛋白的过表达以及多巴胺受体的突变。在基于单只动物试验的实验中，将模拟捕食者的掠过阴影用作威胁刺激，具有不同基因背景的果蝇表现出不同的行为，包括僵住、行动迟缓以及奔跑。我们发现，果蝇中人类突变型帕金蛋白的表达导致行走速度降低以及对掠过阴影的反应性下降。多巴胺受体突变的果蝇也表现出类似的改变，这与患有PD的人类典型的运动和认知缺陷一致。我们还发现了果蝇寿命期间行为选择的年龄依赖性趋势，而多巴胺受体突变果蝇在所有年龄组中都保持其降低的总体反应性。我们的数据表明，单试验行为分析可以揭示突变果蝇中细微的行为变化，这些变化可用于增进我们对疾病发病机制的理解，并有助于评估神经退行性疾病遗传模型的有效性，使我们在弥合果蝇到人类的转化差距方面又迈进了一步。
