Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world, the first being Alzheimer’s disease. Patients with PD have a loss of dopaminergic neurons in the substantia nigra of the basal ganglia, which controls voluntary movements, causing a motor impairment as a result of dopaminergic signaling impairment. Studies have shown that mutations in several genes, such as SNCA, PARK2, PINK1, DJ-1, ATP13A2, and LRRK2, and the exposure to neurotoxic agents can potentially increase the chances of PD development. The nematode Caenorhabditis elegans (C. elegans) plays an important role in studying the risk factors, such as genetic factors, aging, exposure to chemicals, disease progression, and drug treatments for PD. C. elegans has a conserved neurotransmission system during evolution; it produces dopamine, through the eight dopaminergic neurons; it can be used to study the effect of neurotoxins and also has strains that express human α-synuclein. Furthermore, the human PD-related genes, LRK-1, PINK-1, PDR-1, DJR-1.1, and CATP-6, are present and functional in this model. Therefore, this review focuses on highlighting and discussing the use of C. elegans an in vivo model in PD-related studies. Here, we identified that nematodes exposed to the neurotoxins, such as 6-OHDA, MPTP, paraquat, and rotenone, had a progressive loss of dopaminergic neurons, dopamine deficits, and decreased survival rate. Several studies have reported that expression of human LRRK2 (G2019S) caused neurodegeneration and pink-1, pdr-1, and djr-1.1 deletion caused several effects PD-related in C. elegans, including mitochondrial dysfunctions. Of note, the deletion of catp-6 in nematodes caused behavioral dysfunction, mitochondrial damage, and reduced survival. In addition, nematodes expressing α-synuclein had neurodegeneration and dopamine-dependent deficits. Therefore, C. elegans can be considered an accurate animal model of PD that can be used to elucidate to assess the underlying mechanisms implicated in PD to find novel therapeutic targets.
Graphical Abstract
Schematic representation of Parkinson’s disease models in Caenorhabditis elegans. In neurotoxin models, it has been observed that nematodes exposed to neurotoxic agents such as 6-OHDA, MPTP, paraquat, and rotenone can lead to PD impairments like the death of dopaminergic neurons, reduced dopamine levels, and decreased worm survival. In genetic models, mutations in several genes have the potential to increase the probability of PD development. The expression of human LRRK2 (G2019S) can induce neurodegeneration in worms, while the deletion of genes like pink-1, pdr-1, djr-1.1, and catp-6 is associated with behavioral dysfunction, mitochondrial damage, and decreased survival.
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Data Availability Statement
Not applicable.
Abbreviations
- 6-OHDA:
-
6-Hydroxydopamine
- AADC:
-
Aromatic L-amino acid decarboxylase
- ADEs:
-
Anterior deirid neurons
- ATP:
-
Adenosine triphosphate
- C. elegans :
-
Caenorhabditis elegans
- CEPs:
-
Cephalic sensilla neurons
- DAT:
-
Dopamine transporter
- DHE:
-
Dihydroethidium
- DOPAC:
-
3,4-Dihydroxyphenylacetate acid
- DOPAL:
-
3,4-Dihydroxyphenylacetaldehyde
- PD:
-
Parkinson’s disease
- ROS:
-
Reactive oxygen species
- GABA:
-
Y-aminobutyric acid
- GFP:
-
Green fluorescent protein
- ILS:
-
Insulin-like signaling
- KRS:
-
Kufor Rakeb syndrome
- L-DOPA:
-
L-3,4-dihydroxyphenylalanine
- MAO-B:
-
Monoamine oxidase B
- MDA:
-
Malondialdehyde
- mitoUPR:
-
Mitochondrial unfolded protein response
- MPP+ :
-
1-Methyl-4-phenylpyridinium
- MPTP:
-
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- PDEs:
-
Posterior deirid neurons
- SN:
-
Substantia nigra
- TH:
-
Tyrosine hydroxylase
- VMAT2:
-
Vesicular monoamine transporter
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Acknowledgements
We thank the Keizo Asami Institute (iLIKA) and Graduate Program in Biology Applied to Health (PPGBAS) for providing research infrastructure.
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The FACEPE - Fundação de Amparo à Ciência e Tecnologia de Pernambuco (APQ-1223-2.05/22), the FAPESP - Fundação de Amparo à Pesquisa do Estado de São Paulo (2019/14722-4), and the National Council for Scientific and Technological Development (CNPq) financially supported the National Institute of Science and Technology on Molecular Science (INCT-CiMol - 406804/2022-2).
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L.P.D.S., P.G., E.C.G.: original draft, reviewing, editing, and supervision; L.P.D.S., P.G., E.C.G., I.C.O.F., G.J.S.P.: writing, original draft, and editing. P.G., L.A.L.P.: writing, original draft, editing, 3D image design.
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da Silva, L.P.D., da Cruz Guedes, E., Fernandes, I.C.O. et al. Exploring Caenorhabditis elegans as Parkinson’s Disease Model: Neurotoxins and Genetic Implications. Neurotox Res 42, 11 (2024). https://doi.org/10.1007/s12640-024-00686-3
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DOI: https://doi.org/10.1007/s12640-024-00686-3