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  • Writer's pictureQueen's For Parkinson's Kingston

What really causes Parkinson's Disease?

Summary of: “Historical Perspective: Models of Parkinson’s Disease” by Chia, Tan and Chao, 2020

By: Natalie Wilcox

Every paper on Parkinson’s disease begins with some variation of ‘Parkinson’s disease is the second most common neurodegenerative disease… that results in the loss of dopaminergic neurons…. whose cause is not fully known’. However, a paper published in 2020 in the International Journal of Molecular Sciences provides some insight into the causation of the condition by examining historical models. Models are an integral part of the research process as they allow a disease to be induced in healthy tissue so that various treatments and drugs can be tested upon them. The different ways of inducing a disease can give us insight into the foundational cause of the condition. Different organisms can be used to understand different processes.

There are four different types of organisms that are used to explore and test different possible methods. Rodents are often used because they exhibit PD like symptoms when stimulated, are easy to genetically manipulate, but can be relatively expensive. Non-human primates provide the closest model to humans, but are very expensive, have a long life cycle, and are associated with many ethical concerns. For a shorter living organism, where multiple generations can be examined, fish such as zebrafish and organisms such as drosophila are used. These organisms are particularly useful for assessing genetic modifications and phenotypes. The last option is a novel method that turns specified cells (ex. Skin cells) and uses genetic editing to turn them back into stem cells that can be further edited to create ANY cell type. By modifying the genetic factors introduced with these engineered stem cells they can be differentiated into neuronal tissue that can be directly manipulated for extremely specified molecular and genetic study. It is fast, inexpensive and will likely be an extremely successful tool in the study of neurogenetic disorders.

There are two main ways that researchers induce PD in organisms: chemical neurotoxins and genetic modifications that are each found to produce PD-like symptoms. We will first discuss the neurotoxin model. Many of the neurotoxins originate in agricultural chemicals that were found by chance to increase the risk of PD. 6-OHDA damages dopamine neurons by producing harmful compounds when exposed to oxygen. This is particularly noticeable in the dopamine production center (substantia nigra) and the striatum, which is where dopamine acts on the movement centers to initiate smooth movement. Therefore, it is effective in creating the behavior characteristic of the disease. Another chemical MPTP can be used to study the cellular impact of the disease as it crosses the protective blood brain barrier and hinders cellular energy production. The last two neurotoxins, paraquat and rotenone, are both pesticides that were found to be associated with an increase in PD symptoms. Paraquat works by stripping the dopamine neurons of some of their protective barriers. Rotenone on the other hand is one of the most effective producers of PD symptoms due to its impact on the striatum and neurotransmitter production. None of the chemicals perfectly mimic true PD, but they all offer an insight into the contributing factors for the disease.

Genetic models of PD have been useful in understanding the role of genetics in the condition. The impact on the genetic code extends beyond familial inheritance, to understanding the cause of the disease in people with no familial link to PD. LRRK2 and parkin genes, have been found to be linked to the parentally inherited dominant transmission of the disease, while Protein Diglycine mutations are found to be associated with the recessive inheritance. Α- synculins are a protein that has been often found in the nerves of people with PD and may play a role in the the development of Lewy Bodies, or protein clumps associated with PD progression. Each genetic component has some contribution to the overall symptom presentation of PD but none tells the whole story.

Although there is no whole cohesive model for the production of PD pathology this does not mean that each of these models isn’t of significance. Perhaps one is the key, and perhaps it is all of them. There are even models examining the relationship of models on each other. So, when journal articles say that the cause of PD isn’t known, this isn’t necessarily true, we know a lot, we have almost all the puzzle pieces, its just how to arrange them to make the final picture of human Parkinson’s that remains a challenge for scientists.

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