Parnad Basu, Amity University Kolkata
What is Parkinson’s disease?
Parkinson’s disease is a neurodegenerative disorder that affects neurons (dopamine-producing) of substantia nigra. Symptoms of this disease develop slowly over the years and vary from person to person. The cause of Parkinson’s disease is not well known which makes it difficult to cure. However, medications and surgeries are widely used as treatment. Currently, more than 10 million people worldwide have been diagnosed with Parkinson’s.
The recent study:
Scientists have been working nonstop to provide information about Parkinson’s. In a recent study done by scientists at Gladstone Institutes, we have some new information. We all know that mitochondria are the powerhouse of the cell. Researchers have used this information to dive deep to find more about Parkinson’s. In the study, scientists combined timelapse microscopy and correlative light and electron microscopy. They did this to track mitochondria in neurons lacking the fission-promoting protein Drp1. Drp1 is dynamic-related protein 1. It also helps to delineate PINK1 (P TEN induced kinase 1) dependent pathways.
In the case of Drosophila, the loss of PINK1 leads to neurodegeneration and eventually death. PINK1 also increases the fission-fusion balance in a mitochondrion. That’s why Parkin targets Mfn1 and Mfn2 (mitochondrial fusion proteins) when mitochondria are polarized. To understand this more clearly scientists developed neuronal culture and mouse models. It was developed with the deletion of Drp1 in dopamine neurons. This would make it easy to understand how PINK1/Parkin and mitochondrial fission assist mitochondrial quality control.
Brief methods and materials:
- Mice: Group housed mice colony were maintained with 12-hour light and dark cycle.
- Primary neuronal cultures: From early postnatal mouse primary hippocampal cultures were prepared.
- Histology: Mice were anaesthetized with PBS (phosphate-buffered saline) and PFA (paraformaldehyde).
Results of the study:
Results of this study are as amazing as it is crucial. It was found that Drp1KO (Drp1 knockout) elevates PINK1 and Parkin-related engulfment of mitochondria that happens by autophagosomes and produces mitophagosomes. It goes on to produce acidification by lysosomes forming mitolysosomes. This shows that Drp1KO increases mitophagy (selective degradation of mitochondria by autophagy) in neurons. It was found that there are two pathways for Parkin to target mitochondria. In the case of the indirect pathway, OM (outer mitochondrial membrane) plays a very crucial role. At first, depolarized mitochondria accumulate Parkin on their OM. This then goes on to form mitolysosome. And in the direct pathway, mitochondria directly accumulate Parkin.
Previous studies done on PINK1/Parkin-based mitophagy had some limitations. But, in this current study scientists took advantage of decreased mobility and the large size of Drp1KO mitochondria. This helped to visualize key steps of the mitochondrial life cycle. This study also shows that the direct pathway was less acidic and larger compared to the indirect pathway.
Conclusion and questions:
The results of this study define a distinct mitochondrial life cycle in neurons. It also points out mechanisms that permit cells to reuse mitochondria that are damaged. Along with that, it shows that acidified mitolysosomes can have a functional subset of protein which misleads the identification of mitolysosomes as complete mitochondria. However, further studies are needed to understand the functions of PINK1 and Parkin.
Also read: Deforestation causes anthropogenic insect wing polymorphism
Reference:
- Li, H., Doric, Z., Berthet, A., Jorgens, D. M., Nguyen, M. K., Hsieh, I., Margulis, J., Fang, R., Debnath, J., Sesaki, H., Finkbeiner, S., Huang, E., & Nakamura, K. (2021). Longitudinal tracking of neuronal mitochondria delineates PINK1/Parkin-dependent mechanisms of mitochondrial recycling and degradation. Science Advances, 7(32), eabf6580. https://doi.org/10.1126/sciadv.abf6580
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