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Published on: December 28, 2021
Cerebroventricular Microinjections of MPTP on Adult Zebrafish Induces Dopaminergic Neuronal Death, Mitochondrial
1Department of Biology, Faculty of Science, University of Ottawa, Ottawa, ON, Canada.
Abstract:
Mitochondria are dynamic organelles that mediate the energetic supply to cells and mitigate oxidative stress through the intricate balance of fission and fusion. Mitochondrial dysfunction is a prominent feature within Parkinson disease (PD) etiologies. To date, there have been conflicting studies of neurotoxin impact on dopaminergic cell death, mitochondrial function and behavioral impairment using adult zebrafish. Here, we performed cerebroventricular microinjections (CVMIs) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on adult transgenic zebrafish that resulted in significant reductions in dopaminergic neurons within the telencephalon and olfactory bulbs (OB) of Tg(dat:eGFP) fish. Visualization of mCherry and mitochondrial gene expression analysis in Tg(dat:tom20 MLS:mCherry) fish reveal that MPTP induces mitochondrial fragmentation in dopaminergic neurons and the activation of the pink1/parkin pathway involved mitophagy. Moreover, the loss of dopaminergic neurons translated into a transient locomotor and olfactory phenotype. Taken together, these data can contribute to a better understanding of the mitochondrial impact on dopaminergic survivability.
Insights
MPTP neurotoxin causes mitochondrial fragmentation and dopaminergic neuron loss in zebrafish, impacting motor and olfactory functions. This study clarifies mitochondrial roles in Parkinson disease pathogenesis.
Area of Science:
- Neuroscience
- Cell Biology
- Mitochondrial Biology
Background:
- Mitochondrial dysfunction is implicated in Parkinson disease (PD) pathogenesis.
- Previous studies on neurotoxin effects in zebrafish models yield conflicting results.
- Understanding mitochondrial dynamics in neurodegeneration is crucial.
Purpose of the Study:
- To investigate the impact of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on dopaminergic neurons and mitochondrial function in adult zebrafish.
- To elucidate the role of mitochondrial fragmentation and mitophagy in MPTP-induced neurodegeneration.
- To correlate neurochemical changes with behavioral deficits in a zebrafish PD model.
Main Methods:
- Cerebroventricular microinjections (CVMIs) of MPTP in adult transgenic zebrafish (Tg(dat:eGFP) and Tg(dat:tom20 MLS:mCherry)).
- Quantification of dopaminergic neuron loss in the telencephalon and olfactory bulbs (OB).
- Mitochondrial morphology assessment (fragmentation) and analysis of mitophagy-related gene expression (pink1/parkin pathway).
- Behavioral testing for locomotor and olfactory functions.
Main Results:
- MPTP significantly reduced dopaminergic neurons in the telencephalon and OB.
- MPTP induced mitochondrial fragmentation in dopaminergic neurons.
- Activation of the pink1/parkin pathway, indicating mitophagy, was observed.
- Dopaminergic neuron loss correlated with transient locomotor and olfactory deficits.
Conclusions:
- MPTP exposure in zebrafish leads to mitochondrial fragmentation and dopaminergic neurodegeneration.
- The pink1/parkin pathway is activated, suggesting a role for mitophagy in this model.
- Zebrafish models can effectively recapitulate key mitochondrial aspects of Parkinson disease.
- These findings enhance understanding of mitochondrial dysfunction in dopaminergic neuron survival.
