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Eukaryon

A Walk in the Parkin

Allyson Richards
Lake Forest College
Lake Forest, Illinois 60045

Displaying antigens on the surface of the plasma membrane can inform the immune system of the cells status. The discovery of antigens on the plasma membrane in Parkinson’s patients opened the door for a link between autoimmune diseases and PD.

 

Over one million people in the United States alone are living with Parkinson’s Disease9. Parkinson’s is a progressive neurodegenerative disorder that is associated with the loss of movement ability due to a loss of dopamine neurons1. This disease is only really seen in patients who are sixty years of age or older with the primary symptoms being tremors, rigid muscles, and postural instability2,3. It is very uncommon for young adults to be diagnosed. In the brain, there is an extensive amount of neurodegeneration in the substantia nigra and the basal ganglia. These areas of the brain are known for motor function. Unfortunately, there is currently no known cure for Parkinson’s Disease, however, there are treatments to lighten the symptoms3.

            There are many proteins that can point scientists towards the mechanism for this heartbreaking disease. Two major ones are PINK1 and Parkin. The mutated forms of PINK1 and Parkin are known to cause familial Parkinson’s Disease. They also play a role in regulating mitophagy, which is the removal of damaged mitochondria4,5. In the absence of PINK1 and Parkin, there are high levels of mitochondrial antigen presentation (MitAP) on the membrane of damaged mitochondria. Antigen presentation can lead to an immune effect on these cells. However, this effect can lead to antibodies attacking the antigens located on the mitochondria (autoimmune mechanism)6. An article published in Cell by Michel Desjardins called Parkinson’s Disease Related Proteins PINK1 and Parkin Repress Mitochondrial Antigen Presentation looked at how PINK1 and Parkin repress MitAP from mitochondria immune cells in more detail.

            In their study, the researchers focused mainly on the pathway that antigens take to reach the membrane of the mitochondria. Using in vivo mice, they first saw that there was a vacuolar pathway for these antigens. Then, after inhibiting mitophagy, they discovered that it is not responsible for MitAP. Thirdly, the scientists discovered that heat stress induces mitochondrial derived vesicles which is the main pathway for MitAPs. To further prove that autoimmunity is playing a role, the scientists tested OGDH. To do this, they used glycoprotein B (gB) and immunofluorescence to target the mitochondrial matrix.

            In their first study, the scientists focused mainly on how heat stress affects MitAP and the vacuolar pathway being used. Compared to controlled mice, antigen presentation on mitochondria under heat stress was significantly higher. To show what vacuolar pathway was being used, the researchers used MG132, which inhibits proteasomes, and Baf which inhibits lysosomes. Proteasomes and lysosomes are two proteins that degrade damaged proteins7. In other words, it is a pathway that antigens could be using to get on the plasma membrane. However, they discovered that there was still a significant increase of antigens present on the membrane, proving that there is another vacuolar pathway being used.

            Next, the researchers wanted to show that mitophagy is not responsible for MitAP and that PINK1 and Parkin play a major role in repressing this formation. After inhibiting mitophagy under heat stress, there was still a significant increase of MitAP compared to the control group. Along with inhibiting mitophagy, they also inhibited autophagy which is the basic destruction of cells8. Inhibiting autophagy under heat stress also induces a significant increase of MitAP compared to the control group. Thus, proving that mitophagy and autophagy are not responsible for MitAP, because even after inhibiting them, there are still antigens present. The researchers also showed that PINK1 and Parkin play an active role in inhibiting MitAP presentation. After knocking down PINK1, there is a significant increase of MitAP. However, when over-expressing Parkin, the researchers found that there was a significant decrease of MitAP; proving that PINK1 and Parkin repress antigen presentation on the plasma membrane.

            Thirdly, the researchers turned their attention towards heat stress. Heat stress is known to stimulate autophagy. They discovered that heat stress induces mitochondrial derived vesicles (MDVs). These MDVs are the vacuolar pathway that the antigens are using to present themselves on the mitochondria plasma membrane. By using Tom20, which is a mitochondria marker, the researchers were able to see the co-localization of mito-gB and Tom20. Under heat stress, immunofluorescence shows Tom20 and Mito-gB dissociating and localizing in vesicle-like structures. These structures turned out to be MDVs. From the controlled group (37℃), the histogram of Manders’ Coefficient shows a significant decrease of localization under heat stress (45℃).

            To show that Parkinson’s can relate back to an autoimmune disease, the researchers looked at the protein OGDH. OGDH is already linked to the autoimmune disease of PBC which is associated with the presentation of a peptide derived from the mitochondrial matrix. After overexpressing Parkin, the researchers discovered that there was a significant decrease in the amount of OGDH present on the plasma membrane.. After inducing heat stress, knocking out PINK1 significantly increases the amount of OGDH presentation on the plasma membrane. This can help further provide evidence that autoimmunity can play a role in Parkinson’s disease.

            The overall conclusion of the researcher’s findings is that PINK1 and Parkin play an active role in the repression of mitochondria antigen presentation. Surprisingly, the pathway for MitAPs was not mitophagy. In fact, under heat stress, the generation of MDVs was the pathway being used. It was found that PINK1 and Parkin also actively repress the formation of MDVs, therefore decreasing the amount of MitAPs found. In the future, researchers can test all Parkinson’s patients for MitAP to try and relate it back to autoimmune diseases. These discoveries can help to show a mechanistic basis for understanding mitochondrial immune tolerance and related autoimmune disease. Also, identifying PINK1 and Parkin as regulators of the immune system opens many questions and ideas for the development of effective treatments of Parkinson’s.

Richards Fig 1

Richards Fig 1 Key

 

Figure 1. This figure shows how PINK1 and Parkin can affect mitochondrial antigen presentation. It shows that under heat stress, MitAP is not due to mitophagy. Without the presence of PINK1 and Parkin, MitAP does occur. When PINK1 and Parkin are present, there is no antigen presentation on the plasma membrane. Therefore, PINK1 and Parkin play an active role in the repression of MitAP.

 

My approach to this paper was mostly based off my capsule presentation and worksheet. I used all of my resources including the scientific paper itself, the Internet for background research, and Liza for reviewing my paper. After completing this paper, I sent it to Liza multiple times to ensure that I did my very best on it.

 

References

  1. Parkinsons Disease. (n.d.). Retrieved March 30, 2018, from https://www.urmc.rochester.edu/neurosurgery/for-patients/conditions/parkinsons-disease.aspx
  2. Parkinson’s disease. (2015, July 07). Retrieved March 30, 2018, from https://www.mayoclinic.org/diseases-conditions/parkinsons-disease/symptoms-causes/syc-20376055
  3. What Are Common Symptoms of Parkinson’s? (n.d.). Retrieved March 30, 2018, from https://parkinsonsdisease.net/symptoms/
  4. Jones, R. (n.d.). The Roles of PINK1 and Parkin in Parkinson’s Disease. Retrieved March 30, 2018, from http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1000299
  5. Ding, W., & Yin, X. (2012, July). Retrieved March 30, 2018, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3630798/
  6. What Are Autoimmune Disorders? (n.d.). Retrieved March 30, 2018, from https://www.webmd.com/a-to-z-guides/autoimmune-diseases
  7. Proteasome vs Lysosome - What’s the difference? (2017, July 05). Retrieved March 30, 2018, from https://wikidiff.com/lysosome/proteasome
  8. Mandal, A. (2018, February 02). What is Autophagy? Retrieved March 30, 2018, from https://www.news-medical.net/health/What-is-Autophagy.aspx
  9. Boyles, S. (2010, October 04). Parkinson’s: Later Diagnosis, Earlier Death. Retrieved March 31, 2018, from https://www.webmd.com/parkinsons-disease/news/20101004/parkinsons-later-diagnosis-earlier-death#1v

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