PD Animal Models

Neurological disorders can be modeled in animals to recreate specific pathogenic events and behavioral outcomes. The development of animal models of Parkinson's disease (PD) is important to test new neuroprotective agents and strategies. At Creative Biolabs, we are highly experienced in PD animal modeling research.

Background of PD

PD is the second most common neurodegenerative disorder, affecting 1% of the population over the age of 55. The neuropathological hallmark of PD is the formation of eosinophilic Lewy bodies in surviving dopaminergic neurons. With the development of animal models of PD, the study of its pathogenesis has also advanced rapidly. Early models were built using specific dopaminergic neurotoxins. Recently, mutations in the alpha-synuclein gene (and others) have been identified in many PD patients, leading to the development of gene-based models of PD.

Animal models for PD

Animal models of PD have come in various forms over the decades. All of these experimental models continue to be categorized into two main flavors: toxic and genetic.

• Toxin Models

Many pharmacological and toxic agents including reserpine, haloperidol, and inflammogens like lipopolysaccharide have been used over the years to model PD, and the two most widely used are the classical 6-hydroxydopamine (6-OHDA) in rats and 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) in mice and monkeys.

1) The MPTP model

MPTP represents the most important and most frequently used parkinsonian toxin applied in animal models and has a competitive advantage over all other toxic PD models because: (i) it directly causes a specific intoxication of dopaminergic structures and (ii) it induces human symptoms virtually identical to PD. At present, the MPTP mouse model serves as the most useful animal model of PD to study neuropathological and neurochemical changes, basically a consequence of both technical and economic reasons.

2) The 6-OHDA model

6-OHDA is the hydroxyl analogue of the natural neurotransmitter dopamine. 6-OHDA induces ultrastructural changes in non-neuronal cells, e.g., in adrenocortical cells of lizards and rats. The 6-OHDA model induces dopaminergic neuron death with the preservation of non-dopaminergic neurons, whereas the formation of cytoplasmatic inclusions does not occur. The 6-OHDA model with an intranasal injection regimen is more useful for neuroprotective studies, while the regimen of injecting 6-OHDA into the substantial nigra-ventral tegmental area (SN-VTA) complex appears to be a more useful method for testing new pharmacological or cell replacement therapies.

Fig.1 Schematic overview of molecular and intracellular pathways of dopaminergic neurotoxins applied in animal models of PD. (Schober, 2004)

• Genetic Models

Genetic mutations in PD are very rare, accounting for only about 10% of all PD cases. Animal models of these mutations (α-synuclein and LRRK2, autosomal dominant PD) and (PINK1/Parkin and DJ-1, autosomal recessive PD) are important because they represent potential therapeutic targets.

α-Synuclein

Mutations to the α-synuclein gene, which is normally thought to play a role in synaptic vesicle recycling, were the earliest evidence of a genetic link to PD. Two mutations in the α-synuclein gene (A53T, A30P) cause a dominantly inherited form of PD and have been used to create transgenic mice to recapitulate the pathophysiology of PD. Many α-synuclein transgenic mice have been modeled using multiple promoters. In many vertebrate animal models, only mouse prion promoter (mPrP) A53T α-synuclein transgenic mice show the complete α-synuclein pathology observed in humans.

Fig.2 Mechanisms of Autosomal-Dominant PD. (Dawson, 2010)

Currently, existing animal models of PD have greatly contributed to our understanding of the pathogenesis of human disease and potential neuroprotective treatments. Creative Biolabs offers PD animal models and related services based on your research to understand its pathogenesis and test potential treatments. Please feel free to contact us to discuss your project.

References

1. Schober, A. Classic toxin-induced animal models of Parkinson's disease: 6-OHDA and MPTP. Cell and tissue research. 2004, 318(1): 215-224.
2. Dawson, T.M.; et al. Genetic animal models of Parkinson's disease. Neuron. 2010, 66(5): 646-661.