Tiny Fish, Big Hope: Zebrafish Unlocking Secrets to Fight Parkinson’s Disease
Simple Summary
Abstract
1. Introduction
2. History of Zebrafish as a Model Organism
3. Applications in Development and Disease Research
4. Advances in Neurobiology and Imaging
5. Zebrafish as a Model Organism to Study Parkinson’s Disease
6. Inducing Parkinson’s Symptoms in Zebrafish Using Parquat
6.1. MPTP Exposure
6.2. Rotenone Exposure
6.3. Genetic Studies
6.4. Paraquat-Induced Symptoms
6.5. Shared Pathological Mechanisms
6.6. Behavioral Assessments in Practice
6.7. Neurochemical Analyses
7. Advantages of Zebrafish as a PD Model
Success Stories
8. Limitations and Considerations
9. Future Directions
10. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Model Category | Typical Stage Used | Application |
---|---|---|
Neurotoxin (MPTP, Rotenone, Paraquat, 6-OHDA) | Larvae for throughput; Adults for chronic/behavioral | Larvae: imaging & high throughput; Adults: complex motor assays |
Genetic (SNCA, PINK1, Parkin, LRRK2, DJ-1) | Embryo/larva → adult (depending on phenotype) | Early developmental effects in larvae; adult lines for progressive phenotypes |
Environmental (Mn, Pb, pesticide mixtures) | Larvae and adults (dose/time dependent) | Models cumulative, low-dose or chronic exposures; behavioural impact in adults |
Category | Method | Protocol Overview | Key Parameters | Typical Equipment | Validation/Notes |
---|---|---|---|---|---|
Motor | Open-field locomotor assay (adult) | Single fish in arena, recorded 0–96 h post-toxin (MPTP, rotenone) | Distance, velocity, immobility, turn angle, meander | Video camera, arena, tracking software | Validated against DA depletion and TH staining [46,55,56,57,58] |
Motor | Automated larval swimming tracking | Larvae exposed to MPP+ or rotenone; monitored under light/dark cycles | Swim distance, bout counts, thigmotaxis, transitions | Multi-well plates, automated imaging/tracking | Dose–response and drug rescue shown [46,56,57,58] |
Motor | Maze & reward latency tests | Fish trained to reach reward after toxin exposure | Latency, errors, path efficiency, learning curve | Custom maze, video tracking | Cognitive impairments linked to DA release deficits [55,59,60] |
Motor | Kinematic analysis & acoustic startle | High-speed capture of escape/startle; acoustic pulses | Turn duration, angular velocity, startle latency/habituation | High-speed camera, acoustic stimulator | Sensitive to subtle sensorimotor + deficits [46,56,61]. |
Motor | Electrical stimulation (microfluidic) | 6-OHDA larvae; electrical pulses in lab-on-chip | Evoked locomotor amplitude, response frequency | Microfluidic chip, electrodes, video | Validated with Panx1 mutants & TH analysis [58,61] |
Non-motor | Light–dark preference | Fish explore divided tank | Time in zones, transitions, latency | Light/dark box, tracker | Anxiety-like phenotypes observed [55,57,60,62] |
Non-motor | Thigmotaxis | Open field with center/periphery zones | Wall-following, time in center vs. periphery | Arena, tracker | Reliable anxiety measure in PD models [46,58,62] |
Non-motor | Sleep & circadian monitoring | 24 h continuous recording | Sleep duration, latency, fragmentation, circadian phase | Infrared cameras, automated software | Melatonin rescue of sleep deficits shown [55,56,57,62] |
Non-motor | Social interaction/shoaling | Paired/group assays or mirror tests | Interaction time, aggression, shoaling | Dual chamber, video | Rotenone reduces sociality, increases aggression [60,62] |
Non-motor | Olfactory response testing | Odor choice/gradient assays | Latency, preference index, discrimination | Olfactometer, airflow, video | Limited but reported in MPTP/rotenone [46,56] |
Non-motor | Cognitive (conditioning) assays | Classical/operant learning, memory retention | Acquisition, retention, reversal learning | Conditioning chambers, stimulus system | MPTP/rotenone impair memory; rescued by drugs [55,59,60] |
Modeling Approach | Key Phenotypes in Zebrafish | Comparative Advantages vs. Rodent Systems | Limitations | References |
---|---|---|---|---|
Neurotoxin: MPTP, 6-OHDA | Dopaminergic neuron loss; reduced locomotion; erratic swimming; altered gene/protein expression in neurological pathways | Rapid induction of PD-like symptoms; transparent larvae allow real-time imaging; cost-effective and scalable for drug screening | May not fully capture chronic or late-onset features of PD | [24,27,28,31,32,37] |
Neurotoxin: Rotenone, Paraquat | Oxidative stress; mitochondrial dysfunction; progressive dopaminergic neurodegeneration; motor impairments | Mimics environmental toxin exposure in humans; models oxidative stress mechanisms effectively | Toxicity profiles differ from mammals; long-term exposure studies are limited | [31,32,37] |
α-Synuclein transgenic lines | Protein aggregation; Lewy body-like inclusions; dopaminergic cell loss | Directly models hallmark human PD pathology; optical transparency allows tracking of aggregation in vivo | Zebrafish lack endogenous α-synuclein homolog, requiring transgenic approaches | [6,7,34,35,36,91,92] |
PINK1/Parkin knockdown or mutants | Defective mitophagy; dopaminergic neuron vulnerability; motor dysfunction | Conserved mitochondrial pathways; faster assessment of mitophagy compared to rodents | Early-onset PD mutations may not model late-onset disease well | [33,37,46] |
DJ-1 knockdown | Increased susceptibility to oxidative stress; dopaminergic cell loss | Mechanistic insight into oxidative stress pathways in PD | Partial phenotype compared to human PD | [37,91,92] |
LRRK2 mutant lines | Synaptic dysfunction, altered vesicle trafficking, impaired autophagy | Models familial PD mutations; allows rapid in vivo functional assays | Some phenotypes are less pronounced than in mammalian models | [46] |
Other genetic knockdowns (dj1, pink1, prkn) | Familial PD-like phenotypes; altered dopaminergic pathways | Stronger phenotypic expression than rodents in some cases; genetic tractability | Require validation against human disease heterogeneity | [37,91] |
Drug screening/high-throughput assays | Behavioural rescue; reduced aggregation; restored mitochondrial function | Transparent embryos allow in vivo pharmacology; a scalable, cost-effective alternative to rodent models | Differences in metabolism and lifespan limit direct translation | [93,94,95,96] |
Comparative advantages | Real-time imaging; rapid development; high-throughput screening | Cost-effective, ethically favourable, and genetically tractable | Short lifespan, lack of some human-specific proteins (e.g., α-synuclein) | [7,46,89,97] |
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Bangeppagari, M.; Manjunath, A.; Srinivasa, A.; Lee, S.J. Tiny Fish, Big Hope: Zebrafish Unlocking Secrets to Fight Parkinson’s Disease. Biology 2025, 14, 1397. https://doi.org/10.3390/biology14101397
Bangeppagari M, Manjunath A, Srinivasa A, Lee SJ. Tiny Fish, Big Hope: Zebrafish Unlocking Secrets to Fight Parkinson’s Disease. Biology. 2025; 14(10):1397. https://doi.org/10.3390/biology14101397
Chicago/Turabian StyleBangeppagari, Manjunatha, Akshatha Manjunath, Anusha Srinivasa, and Sang Joon Lee. 2025. "Tiny Fish, Big Hope: Zebrafish Unlocking Secrets to Fight Parkinson’s Disease" Biology 14, no. 10: 1397. https://doi.org/10.3390/biology14101397
APA StyleBangeppagari, M., Manjunath, A., Srinivasa, A., & Lee, S. J. (2025). Tiny Fish, Big Hope: Zebrafish Unlocking Secrets to Fight Parkinson’s Disease. Biology, 14(10), 1397. https://doi.org/10.3390/biology14101397