Animal Models of Parkinson's Disease

Current Research of Parkinson’s Disease

Parkinson's disease is the second most common (after Alzheimer's disease) neurodegenerative disease characterized by movement dysfunctions (commonly tremor and rigidity) and multiple non-motor features such as depression, cognitive impairment, somnipathy. Parkinson's disease is more popular among elders over 60 years old although Adolescent Parkinson's has been reported.

Over these decades, great progress has been made in neuropathological and pathophysiological mechanism exploration and efficient therapy development of Parkinson's disease. A typical pathophysiology feature of Parkinson's disease is the alteration of biological activity in the brain, especially the accumulation of intracellular α-synuclein, leading to neuronal loss or death (mainly dopaminergic neurons) in substantia nigra and a significant decrease of dopamine in the striatum. Possible mechanisms of neuron loss or death in Parkinson's disease have been identified, mainly including clustering or oligomerization of α-synuclein in Lewy bodies, microglia-induced neuroinflammation, and mitochondrial dysfunction, and oxidative stress. Primary pharmacotherapy for Parkinson's disease is dopamine-based, such as Levodopa, dopamine agonists, and monoamine oxidase-B inhibitors. More recently, novel therapies, including gene therapy, cell-based therapies, and neuroprotective treatments, also have been developed for the effective treatment of Parkinson's disease.

Fig.1 Molecular mechanisms involved in Parkinson's disease. (Poewe, 2017)

Animal Models of Parkinson’s Disease

To fully explore and elaborate neuropathological pathways and develop more effective treatments, a range of convenient animal models that can simulate different aspects of human Parkinson's disease are required. A variety of strategies for Parkinson's disease animal modeling have been put forward, which are generally categorized into the neurotoxin-based approach and genetic animals.

• Neurotoxin-based animal models of Parkinson's disease

Neurotoxin Parkinson's models are the most classical and widely used in neuropathology research. Compared with genetic animal models, these animals can be easily established, which are made by systemic or local administration animals, rodents, or non-primates, with drugs that can induce selective degeneration of nigrostriatal neurons. The commonly used neurotoxic animal models include:

Fig.2 Pathogenesis of toxin-induced models. (Blesa, 2016)

• 2,4,5-trihydroxyphenethylamine (6-OHDA)-induced Parkinson rat

Local injection 6-OHDA to rats can reproduce the damage to the nigrostriatal dopamine pathway, SNpc neuronal loss, and behavioral deficits, without affecting other areas of the brain.

• Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson animal

This is the gold standard model of neurotoxin-based Parkinson animal modeling since it simulates characteristics of Parkinson's disease in many aspects, including damage to the nigrostriatal dopamine pathway, SNpc neuronal loss, neuroinflammation, and oxidative stress.

• Pesticide/herbicide-induced models

N, N-dimethyl-4-4-4-bypiridinium (Paraquat, an herbicide), and rotenone (both an herbicide and insecticide) are also used in Parkinson modeling. Paraquat induces damage to the dopaminergic system through oxidative stress. Rotenone is highly lipophilic and can easily penetrate the blood-brain barrier, which can induce rat, not mouse or primate, loss of nigrostriatal DA neurons, oxidative stress, and α-synuclein aggregation.

• Transgenic animal models of Parkinson's disease

In addition to those useful neurotoxin-induced animal models, a series of transgenic animal models also have been developed in recent years by gene manipulating technology.

• α-synuclein transgenic mice: these transgenic mice models are relatively limited since no significant nigrostriatal degeneration has been detected.
• Leucine-rich repeat serine/threonine kinase 2 (LRRK2) mutation rodent animal: although α-synuclein accumulation, motor disfunction, and striatal dopamine decrease have been detected in these transgenic animals, no functional loss of the nigrostriatal dopaminergic neurons was found.
• PTEN-induced putative kinase 1 (PINK1) mutations: parkin or PINK1 mutations are common causes of autosomal recessive Parkinson's disease. Prkn or PINK1 knockout mouse shows a reduced striatal dopamine level in an age-dependent manner, but no dopaminergic neuron abnormality and Lewy bod formation.
• DJ-1 mutation: DJ-1 knockout mouse is characterized by striatal dopamine decrease and hypokinesia, but no loss of SNpc dopaminergic neurons.

Fig.3 Genetic animal models in Parkinson's disease. (Blesa, 2016)

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References

1. Poewe, W.; et al. Parkinson disease. Nature reviews. Disease Primers. 2017, 3: 17013.
2. Blesa, J.; et al. Animal Models of Parkinson’s Disease. In: Challenges in Parkinson's Disease. 2016, pp: 195-216.
3. Konnova, E.A.; Swanberg, M. Animal Models of Parkinson’s Disease. In: Parkinson’s Disease: Pathogenesis and Clinical Aspects. 2018, pp: 83-106.