James Parkinson revealed a detailed description of six patients with shaking palsy in 1817 and after his death, the mentioned description known as Parkinson's disease (PD), which is now the most common neurodegenerative disorder after Alzheimer's disease. The pathological hallmark of PD is the degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc). The loss of this neuronal population results in functional imbalances in the nigrostriatal pathway, leading to lowering the level of dopamine (DA) in the striatum. This leads to motor dysfunction and the development of the classical symptoms of PD. Motor symptoms including resting tremor, bradykinesia, and rigidity of skeletal muscle, postural instability, stooped posture, and freezing of gait are clinical symptoms in PD. Furthermore, non-motor symptoms such as cognitive and behavioral problems, besides sensory impairments are seen in the patients. The prevalence of PD is approximately 0.3 % in the general population in developed countries and affects about 1% of those older than 60 and it is unusual to occur before the age of 50. Notably, men are at higher risk than women.
Fig.1 The dopaminergic neuron and the nigrostriatal pathway. (Lopes, 2017)
Importance of In Vitro Models in PD
Animal models are useful for investigating PD progression as they are amenable to behavioral tests. However, as humans are the only species that develop neurodegenerative disorders, it is necessary to induce dopaminergic damage and/or LB pathology in these models. To date, no model has recreated the full spectrum of PD, which makes it difficult to evaluate molecular mechanisms and translate these findings to humans. In vitro models present a controlled environment that facilitates investigations of molecular and cellular pathophysiological mechanisms of dopaminergic degeneration in PD and the screening of potential therapeutics.
Fig. 2 In vitro models of Parkinson's disease. (Lopes, 2017)
Application of In Vitro Models in PD Research
PD is still an incurable disease, with current treatments being palliative and only addressing the symptoms. Hence, to date, there are no disease-modifying therapies that can stop or slow PD progression. This is mainly attributed to the lack of understanding regarding the pathogenic process underlying dopaminergic degeneration. A large amount of research data regarding PD pathophysiological mechanisms have been obtained using in vitro experimental models, which provide evidence and hypotheses about the initial steps of PD pathology.
Examples of discoveries in PD research using in vitro models:
A-synuclein modulation in DA toxicity.
The involvement of PINK1, PARKIN, and DJ-1 in mitochondrial dysfunction, regarding mitochondrial fragmentation.
The neuroprotective role of DJ-1 protein, and how its dysfunction can lead to toxic processes in PD.
Mutation in LRRK2 gene (e.g., G2019S) increases susceptibility to apoptosis and proteasome stress.
Hence, it is clear that in vitro models are useful for the study of PD pathogenic mechanisms and have a clear and essential place among the battery of models available for use in PD studies.
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Lopes, F. M., et al. Mimicking Parkinson's Disease in a Dish: Merits and Pitfalls of the Most Commonly used Dopaminergic In Vitro Models. Neuromolecular Med. 2017, 19(2-3): 241-255.