Over 90,000 people are diagnosed with Parkinson’s disease every year. This progressive neurodegenerative disease slowly reduces control of one’s movement until that control is lost completely. In the final stages, one is bedridden and soon dies from numerous issues often including a loss of respiratory control. In recent years, researchers have been working tirelessly to establish more effective methods of treatment for this illness, but so far they have only been able to slow the disease’s progression. They utilize a chemical substrate for dopamine called L-Dopa to replenish the lost dopamine reserves that impair movement. But eventually, the body loses the mechanisms to produce dopamine, so the L-Dopa fails to be effective. New methods of treatment need to be procured by further analyzing the networks of this disease.
Parkinson’s Disease is characterized by the build-up of misfolded alpha-synuclein proteins that function with presynaptic transmission in the neurons. Alpha-synuclein overexpression inhibits neurotransmitter release while underexpression prevents vesicle formation. This protein works heavily in vesicular transport. Because Parkinson’s disease is often coupled with dementia (which impacts long-term memory formation), experts concluded that AMPA receptors involved in short-term memory must be dwelling in the ER so they could locally diffuse into the membrane in microseconds. A SNARE protein is involved in the docking of vesicles to the cell membrane. Ykt6 is an R-SNARE(Arginine SNARE) involved in AMPA receptor vesicle docking, glutamate vesicle docking, and autophagy that is highly evolutionarily conserved. This conservation marks the protein as important for core biological processes that are shared among the homologous species and it caught the eye of Dr. Kaitlyn McGrath and her research team. In their research, the team focused on using PD models in yeast, worms, and human cells (HeLa cells). This research noticed that the Ykt6 model is phosphorylated by PRCKi, a protein kinase, and dephosphorylated by CaN phosphatase. The team concluded that this phosphorylation of the R-SNARE protein led to conformational changes that triggered the open or closed conformation in the cytosolic state. This is important because Ykt6 is only active in its open conformation, so when it is closed it will fail to associate with the membrane it is trying to dock a vesicle to. Without this association, it will reduce the efficiency of autophagy processes. These processes protect against alpha-synuclein buildup by digesting protein aggregates in the cell. So mutations in the docking site of Ykt6 or the two enzymes regulating its phosphorylation will create an imbalance in the amount of vesicle docking and allow for the buildup of protein aggregates in alpha-synuclein. If there was a way to target the hippocampus and minimally regulate Ykt6 directly there could be an approach to treating the disease in this research. However, that data has yet to be uncovered.
Another experimental approach to treat Parkinson's comes from attempting to replace the dead dopamine-producing cells with cells that are induced to be pluripotent stem cells. While stem cells do not lead to a reduction in misfolded alpha-synuclein protein aggregates, they in theory could reset the clock on the death of dopamine neurons by differentiating into new neurons. While these stem cells still have the genes that lead to a buildup of alpha-synuclein, those mutations don’t become detrimental until decades have passed. Some of those possible mutations, like a mutated Ykt6 protein or mutations in any of its phosphorylation-regulating enzymes could be detrimental to autophagosomal processes. These autophagic processes are useful because they clean up blockages in the cell, for example, alpha-synuclein protein aggregates would most likely be reduced with increased autophagy. However, autophagy also regulates numerous apoptosis pathways, so targeting an increase in its function is a riskier treatment compared to the stem cell approach. The stem cell approach began when Parkinson's patients had anonymous fetal donors of mesenchymal dopamine stem cells but this approach was difficult to make clinically viable due to the low availability of fetal tissues and the high variability of their proteins and the host body’s reaction towards them. The solution to this came when Yamanaka factors were discovered that rewrote living cells back to their pluripotent stem forms. Now patients can reprogram their own cells using chemical cocktails that mimic the fetal environment and Yamanaka factors to regenerate their own failing dopamine neurons. But, this differentiation is not always properly controlled and tumors or incorrectly developed cells often appear in laboratory studies. The treatment is also very invasive and this risk is often not worth it due to the slower progressive nature of Parkinson's. These caveats prevent the clinical application of stem cell treatments in the brain.
Compared to stem cell treatments, Dr. McGrath’s team’s work seems more likely to develop clinical applications of their research compared to the stem cell movement. This is because, with enough specificity, neuroprotectant mechanisms could be established to limit alpha-synuclein aggregates with possible applications of autophagic systems including Ykt6. The chemicals also are less invasive than the brain surgery required for stem cell implementations. In my opinion, the long-term effects of reduced protein aggregates more effectively cure the disease compared to a redistribution of degenerating dopamine neurons. However, both treatments need improvement in order to be used in a controlled clinical setting accounting for human variability. The stem cell research needs a way to reduce the invasive and unpredictable nature of stem cell procedures and outcomes while McGrath’s team needs to research other autophagic proteins and processes that are disrupted in Parkinson’s. Both of those treatments would likely stop the disease at the core rather than postpone it like the current treatment L-Dopa does. In cases of severe or late-stage Parkinson’s disease, these two possible treatment methods could be paired together to save someone’s life. Because of the newfound attention to this disease from a globally aging population, a successful treatment plan to eliminate the disease has great potential for development.
McGrath, K., Agarwal, S., Tonelli, M., Dergai, M., Gaeta, A. L., Shum, A. K., Lacoste, J., Zhang, Y., Wen, W., Chung, D., Wiersum, G., Shevade, A., Zaichick, S., van Rossum, D. B., Shuvalova, L., Savas, J. N., Kuchin, S., Taipale, M., Caldwell, K. A., … Caraveo, G. (2021). A conformational switch driven by phosphorylation regulates the activity of the evolutionarily conserved SNARE YKT6. Proceedings of the National Academy of Sciences, 118(12), 1–12. https://doi.org/10.1073/pnas.2016730118
Parmar, M. (2018, January 8). Towards stem cell-based therapies for Parkinson’s disease. The Company of Biologists. https://journals.biologists.com/dev/article/145/1/dev156117/48713/Towards-stem-cell-based-therapies-for-Parkinson-s
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