Parkinson’s Disease: A New Avenue for Drug Development

     Neurodegenerative Diseases affect millions of people worldwide and your chances only go up as you age. Parkinson’s Disease (PD) is the second most prevalent neurodegenerative disease behind Alzheimer’s affecting ~10 million worldwide. PD is mainly a movement disorder causing tremors in the extremities. As the disease progresses tremors worsen along with the development of a stooped posture, shuffling gait, gastrointestinal issues, and many cases progress into dementia¹. Simply put, these effects are caused by the accumulation of Lewy bodies (aggregates mainly composing of the protein α-synuclein) in dopamine producing neurons (dopaminergic neurons). These Lewy bodies affect the neuron’s ability to produce dopamine along with negatively affecting other cellular functions. There are no current cures for PD, but there are a host of treatments to offset symptoms. One of the most successful of these treatments is dopamine injections which help compensate for the dysfunction of the affected neurons².

https://www.labiotech.eu/medical/axovant-parkinsons-disease-gene/

    Research and drug development for PD has focused mainly on the main culprit of the disease, dopaminergic neurons.  However, there are many other cell types in the brain which all interact with each other. Astrocytes have recently become of interest as drug targets for neurodegenerative disease. Astrocytes perform many roles in the brain and work directly with neurons to keep them healthy and functional. They provide metabolic and structural support, are involved in the blood brain barrier, contribute to neuroinflammation, and take up and degrade extracellular debris including α-synuclein. In fact, reactive astrocytes are a key factor in PD development³. To study the interaction of astrocytes and dopaminergic neurons Domenico et al. employed a co-culture system using induced pluripotent stem cells (iPSC). These stem cells are made by taking an adult cell and transfecting them with four specific genes. These genes help the cells revert to a stem cell state wherein they can become any type of cell, a state similar to that of early embryos. The resultant stem cells were then induced to become either dopaminergic neurons or astrocytes. The use of iPSC allows us to create cells which will have the disease of any patient. 

(Domenico et al. 2019)

    This co-culture system allows us to study the interactions between astrocytes and dopaminergic neurons with and without PD. Using this system, we have been able to detect astrocyte involvement in the progression of PD. Most notably is their role in the accumulation of Lewy bodies. When healthy astrocytes and healthy neurons are co-cultured there is no evident accumulation of Lewy bodies. To see if astrocytes with PD could drive disease a co-culture was done with PD astrocytes and healthy neurons. In this experiment not only were Lewy bodies detected but the survival of dopaminergic neurons was decreased. This suggests that dysfunctional astrocytes contribute to the development of PD. A final co-culture was set up using PD neurons and healthy astrocytes to see if astrocytes were able to offset the dysfunction of diseased neurons. This resulted in a significantly lower accumulation of Lewy bodies and increased survival of neurons⁴.

     At the time of writing this blog there are only a few studies that have been published studying astrocyte interactions with dopaminergic neurons in PD. There is evidence that astrocytes actively exchange α-synuclein, the main component of Lewy bodies, with dopaminergic neurons and degrade it. PD astrocytes have varying degrees of impairment in autophagy and lysosomal function meaning that they are not as able to destroy and discard unwanted or dysfunctional proteins and cellular components⁵. Astrocytes have also been shown to be mitochondrial donors to neurons in another model of PD. Dysfunctional mitochondria are often implicated in PD and the donation of healthy mitochondria to dopaminergic neurons significantly offset PD related phenotypes in dopaminergic neurons⁶.

    The evidence of astrocyte involvement in PD opens the doors to new research into drug development. We may design drugs to target astrocytes to slow or stall the progression of not only PD but other neurodegenerative diseases. The co-culture system using iPSC also allows us a more compete picture for study neurodegenerative diseases.

By Meagan Medley, a Master of Medical Science Student at the University of Kentucky

  References

 1.  Aflaki, E., Stubblefield, B. K., Mcglinchey, R. P., Mcmahon, B., Ory, D. S., & Sidransky, E. (2020). A characterization of Gaucher iPS-derived astrocytes: Potential implications for Parkinson's disease. Neurobiology of Disease, 134, 104647. doi:10.1016/j.nbd.2019.104647

2.  Chaudhuri, K. R., & Schapira, A. H. (2009). Non-motor symptoms of Parkinson's disease: Dopaminergic pathophysiology and treatment. The Lancet Neurology, 8(5), 464-474. doi:10.1016/s1474-4422(09)70068-7

3.   Booth, H. D., Hirst, W. D., & Wade-Martins, R. (2017). The Role of Astrocyte Dysfunction in Parkinson’s Disease Pathogenesis. Trends in Neurosciences, 40(6), 358-370. doi:10.1016/j.tins.2017.04.001

4.   Domenico, A. D., Carola, G., Calatayud, C., Pons-Espinal, M., Muñoz, J. P., Richaud-Patin, Y., . . . Consiglio, A. (2019). Patient-Specific iPSC-Derived Astrocytes Contribute to Non-Cell-Autonomous Neurodegeneration in Parkinson's Disease. Stem Cell Reports, 12(2), 213-229. doi:10.1016/j.stemcr.2018.12.011

5.  Aflaki, E., Stubblefield, B. K., Mcglinchey, R. P., Mcmahon, B., Ory, D. S., & Sidransky, E. (2020). A characterization of Gaucher iPS-derived astrocytes: Potential implications for Parkinson's disease. Neurobiology of Disease, 134, 104647. doi:10.1016/j.nbd.2019.104647

6. Cheng, X., Biswas, S., Li, J. et al. (2020) Human iPSCs derived astrocytes rescue rotenone-induced mitochondrial dysfunction and dopaminergic neurodegeneration in vitro by donating functional mitochondria. Transl Neurodegener 9, 13. https://doi.org/10.1186/s40035-020-00190-6