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Deep Dive: How do genetic and toxin studies in animal models help us understand Parkinson’s disease?

According to the World Health Organisation, disability and mortality from Parkinson’s disease (PD) are increasing faster than for any other neurological disorder. With cardinal symptoms of tremor, bradykinesia, and stiffness, the development of PD significantly deteriorates a person’s physical quality of life. While much has been revealed by studying human PD patients, human clinical and observational studies provide insight insofar as they are correlational, not to mention they only allow for studying late stage PD when symptoms manifest. To establish causative relationships or to understand the pathogenesis of PD, researchers are instead turning their attention to non-human models. By studying animal models, within ethical standards, we can investigate the pathogenesis of PD, genetic risk factors, methods of prevention, and the efficacy of therapeutic interventions. Among animal PD models, genetic and toxin studies have contributed most in our understanding of the disease. In this post, we shall take a deep dive into literature and compare and contrast genetic and toxin studies, extracting valuable insights from PD models.

Toxin models produce the symptoms of PD by the injection of neurotoxins, often targeting nigrostriatal dopamine (DA) neurons, causing their rapid degeneration.

PD animal models can be generated with toxins and genetic manipulation. While both aim to induce PD in these animals, the nature of their pathogenesis differs. In either case, the symptoms of PD are replicated, albeit to varying extents and in different timescales. Toxin models produce the symptoms of PD by the injection of neurotoxins, often targeting nigrostriatal dopamine (DA) neurons, causing their rapid degeneration. On the other hand, genetic manipulation of animals allows the production of an animal model line that express mutant form of a gene of interest – often these genes are those that are indicated in hereditary familial PD. As we shall see, genetic and toxin studies complement each other and allow us to comprehensively investigate the nature and progression of PD.

For toxin studies, there are a diverse portfolio of neurotoxins with different mechanisms of action and effects, e.g., 6-OHDA, MPTP (Jagmag et al, 2015). Ultimately, the aim of neurotoxins is to rapidly induce PD-like symptoms in animals. 6-OHDA is a selective neurotoxin found to accumulate in DA neuron cytosols. They induce two toxic effects – accelerate the production of free radicals, e.g., H2O2, and inhibit complexes I and IV in the electron transport chain. MPTP is a precursor of neurotoxin MPP+ that causes DA cell death in the nigrostriatal pathway, as it has high affinity to plasma membrane DA transporters. Once inside the cell, MPTP inhibits complex I in the mitochondria, depleting DA cells of ATP. For instance, both 6-OHDA and MPTP are used in rodents. 6-OHDA and MPTP kill DA neurons in the time-scale of 1-3 weeks in rodents, leading to massive loss of DA neurons depending on the dosage and administration frequency. Therefore, toxin studies can rapidly produce PD-like DA neuron loss, allowing very accelerated manifestation of PD symptoms in these rodent models.

In addition to rodents, monkeys are also used in studying PD. One of the observations in human PD patients is that an essential protein abundant in the brain – alpha-synuclein – aggregates in an insoluble form in neurons. The use of MPTP in babboons has been demonstrated to induce alpha-synuclein deposits, as demonstrated by Kowall et al (2000) with immunohistochemistry. Thus, MPTP-babboon models allow us to assess the contributions, if any, of alpha-synuclein to PD progression. In toxin animal models, the extent of DA neuron loss mimics that in late-stage PD. Thus, toxin studies tend to be used for studying late-stage PD and efficacy of treatments. For instance, Lu et al (2014) injected 6-OHDA into GFP-labelled DA neurons. They found transport dysfunction after 6-OHDA injection, followed by microtubule disruption and autophagy before DA cell death. However, this transport dysfunction was blocked by application of anti-oxidants. Hence, they concluded that transport dysfunction plays a significant role in axonal degeneration, which contributes to the development of PD.

Nonetheless, toxin studies also have some caveats. Firstly, toxin models provide relatively little mechanistic insight to PD pathogenesis. PD develops gradually over a long time in human patients, which cannot be replicated with toxins, which produce PD-like symptoms rapidly. Furthermore, toxin studies do not allow us to study the prevention of PD, as administration of a sufficient dose of neurotoxins will indiscriminately induce PD-like symptoms. Thirdly, whether toxin studies faithfully replicate the molecular correlates/mechanisms remain to be seen. Rodents injected with 6-OHDA and MPTP do not form Lewy bodies, which is believed to be an essential step of pathogenesis in human PD. Though using MPTP in monkeys produces Lewy body-like alpha-synuclein structures, the practical difficulties of using monkeys in experiments limits the popularity of their use in literature. Therefore, using toxin studies alone cannot reveal everything about PD.

A genome-wide association studies identified 28 independent genetic variants across 24 loci that seem correlated with the development of PD, including SNCA, which is the gene for alpha-synuclein protein.

Moving onto genetic models, there has been promising results in recent years in identifying important genes that may play a role in PD pathogenesis. To give an example, a meta-analysis of genome-wide association studies by Nalls et al (2014) identified 28 independent genetic variants across 24 loci that seem correlated with the development of PD, including SNCA, which is the gene for alpha-synuclein protein. While these genetic association studies are correlational and that it is unclear whether these are essential drivers or helper genes, the modelling of PD with genetic manipulation has been successful and predominant in rodents.

With respect to genetic models, SNCA mutants are the most studied variants. From studying hereditary familial PD, variants of SNCA is associated with an increased risk of PD. SNCA encodes alpha-synuclein, a protein that regulates the trafficking of synaptic vesicles and neurotransmitter release, and which is a major component of Lewy bodies. It was found the overexpression of alpha-synucelin protein has been shown to induce loss of DA neurons, and cause motor impairment in both mice and rats (Oliveras-Salvá et al, 2013). Janezic et al (2013) produced a unique transgenic mouse line with bacterial artificial chromosome expressing the complete human SNCA locus – producing wild-type human alpha-synuclein – at disease-relevant levels. In this new transgenic model, there were early-onset circuit-specific deficits in DA neurotransmission, associated with altered vesicular distribution in DA axons of the dorsal striatum. Interestingly, the motor phenotype and DA neuron loss appeared independent of alpha-synuclein aggregation, but associates with the presence of soluble high molecular-weight alpha-synuclein proteins.. As such, PD-related phenotypes may not be driven by progressive protein aggregation, but in prior DA neurotransmission. This new transgenic mouse line allows progressive and gradual investigation of the cellular and pathogenetic basis of PD. However, while many models have been developed with alpha-synuclein, its exact function is still not established. The use of genetic models allows progressive and natural pathogenesis, which more closely mimics human PD pathogenesis. Its gradual progression provides opportunities for us to study lifestyle interventions, mechanisms of pathogenesis, and prevention efficacy.

In conclusion, animal toxin and genetic models are two common ways to model PD. Toxin and genetic models have complementary strengths and caveats, and so the combined use of both models running in parallel allows the entire temporality, progression and intervention of PD to be studied. toxin studies allow us to answer questions towards the late-stage of PD, e.g., whether a particular drug treatment is effective once so-and-so protein has been identified and accumulated beyond a certain level, while genetic studies help us uncover the natural progression of PD, and helps us answer whether a gene, when isolated, contributes to PD genesis. Alpha-synuclein and its parent gene SNCA are just one of many molecular and genetic substrates understood increasingly more through animal models. Regardless, difficulties remain in the field of PD modelling – for instance, both models do not entirely faithfully mimic human PD, but only various aspects of it. Not to mention, neurotoxins and genetic studies should not be idealised as simple isolation studies, but to bear in mind that there may very well be unintended side effects and uncontrolled for toxicity. In addition to DA transporters, 6-OHDA lesion of DA neurons overactives NAergic neurons with irregular discharge patterns (Wang et al., 2009), suggesting that the influence of DA neurons may be exaggerated in 6-OHDA-lesioned rodents. Fundamentally, mice are different from humans and the amount of transferrable knowledge may be limited, considering their differences. Furthermore, the repertoire of investigations in PD models should be expanded. Other areas that are being investigated includes olfactory dysfunction, cognitive impairment and cardiac sympathetic denervation, and non-DA related pathogenesis.


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  3. Kowall, N. W., Hantraye, P., Brouillet, E., Beal, M. F., McKee, A. C., & Ferrante, R. J. (2000). MPTP induces alpha-synuclein aggregation in the substantia nigra of baboons. Neuroreport, 11(1), 211–213.

  4. Lu, X., Kim-Han, J.S., Harmon, S. et al. The Parkinsonian mimetic, 6-OHDA, impairs axonal transport in dopaminergic axons. Mol Neurodegeneration 9, 17 (2014).

  5. Nalls, M. A., Pankratz, N., Lill, C. M., Do, C. B., Hernandez, D. G., Saad, M., DeStefano, A. L., Kara, E., Bras, J., Sharma, M., Schulte, C., Keller, M. F., Arepalli, S., Letson, C., Edsall, C., Stefansson, H., Liu, X., Pliner, H., Lee, J. H., Cheng, R., … Singleton, A. B. (2014). Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nature genetics, 46(9), 989–993.

  6. Oliveras-Salvá, M., Van der Perren, A., Casadei, N., Stroobants, S., Nuber, S., D'Hooge, R., Van den Haute, C., & Baekelandt, V. (2013). rAAV2/7 vector-mediated overexpression of alpha-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration. Molecular neurodegeneration, 8, 44.

  7. Janezic, S., Threlfell, S., Dodson, P. D., Dowie, M. J., Taylor, T. N., Potgieter, D., Parkkinen, L., Senior, S. L., Anwar, S., Ryan, B., Deltheil, T., Kosillo, P., Cioroch, M., Wagner, K., Ansorge, O., Bannerman, D. M., Bolam, J. P., Magill, P. J., Cragg, S. J., & Wade-Martins, R. (2013). Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model. Proceedings of the National Academy of Sciences of the United States of America, 110(42), E4016–E4025.

  8. Wang, T., Zhang, Q. J., Liu, J., Wu, Z. H., and Wang, S. (2009). Firing activity of locus coeruleus noradrenergic neurons increases in a rodent model of Parkinsonism. Neurosci. Bull. 25, 15–20.

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