Researchers at The Walter and Eliza Hall Institute of Medical Research in Australia have discovered new details about the human PINK1 protein, shedding light on its structure and activation process.
This discovery, published in Science, could play a crucial role in the future of Parkinson’s disease treatment.
Understanding Parkinson’s Disease and the Role of PINK1
Parkinson’s disease is a neurodegenerative disorder that affects movement and is estimated to impact around 10 million people worldwide. While the exact cause of the disease remains unknown, scientists believe it results from a combination of genetic and environmental factors.
One of the key genetic contributors is a mutation in the PINK1 (PTEN-induced putative kinase 1) gene. PINK1 plays a crucial role in mitochondrial health, acting as a quality control mechanism to remove damaged mitochondria. As Sylvie Callegari, PhD, senior research officer at The Walter and Eliza Hall Institute, explained:
“PINK1 [protein] acts as a beacon for damaged mitochondria, famously known as the ‘powerhouse of the cell.’”
Callegari described how PINK1 detects damage and initiates the cleanup process:
“PINK1 senses this damage and docks to the surface of mitochondria. Once positioned on the mitochondrial surface, PINK1 becomes active and seeks out a small protein known as ubiquitin and marks it. These marked versions of ubiquitin are a very specific signal that initiate the clean-up of damaged mitochondria, preventing them from becoming toxic to the cell.”
Without functional PINK1, defective mitochondria accumulate, leading to cellular toxicity and the death of neurons. Since brain cells require high energy levels, they are particularly vulnerable to this process, ultimately leading to Parkinson’s disease.
Overcoming Challenges to Study PINK1
The challenge of studying PINK1’s role in human cells stemmed from its scarcity, prompting scientists to turn to insect PINK1 for research. While this method allowed for larger quantities, it could not uncover the full activation process.
The researchers cultivated nearly 10 litres of cells and employed cryo-electron microscopy to tackle this challenge. “Until now, scientists had been studying insect PINK1 because it is possible to produce it in large amounts,” said Callegari.
“However, we were never able to see how PINK1 docks to the mitochondrial surface, which is the important step that precedes its activation.”
How PINK1 Functions
The study identified four key steps in PINK1’s function:
- Sensing mitochondrial damage
- Attaching to the damaged mitochondria
- Tagging ubiquitin
- Recruiting Parkin to recycle damaged mitochondria
Callegari emphasised the uniqueness of PINK1’s role in mitochondrial maintenance:
“PINK1 is special because it can alter the ubiquitin tag by placing an additional marker on it — it basically tags the tag. This alteration is a very specific signal that initiates the disposal of the entire mitochondria.”
When PINK1 is mutated, this process fails, leading to toxic mitochondrial buildup and, ultimately, neuronal death. As Callegari put it:
“When PINK1 is mutated, it cannot perform its signalling function, and so mitochondria are not effectively cleaned up. Defective mitochondria are toxic to cells, resulting in cell death. The death of neuronal cells in the brain causes Parkinson’s disease.”
A Step Closer to New Treatments
The recent discovery of PINK1’s structure provides a solid foundation for advancing targeted therapies for Parkinson’s disease.
Researchers can now focus on creating drugs that boost the protein’s activity. “Ideally, we want to design a drug that makes PINK1 more active, but without the ability to see PINK1, it is very hard to develop a drug to do this,” Callegari said.
“Now that we can see PINK1, we have the blueprint that we need to improve its activity.”
While experimental drugs to increase PINK1 activity are already being tested, the exact mechanisms of these drugs remain unclear. The new study’s structural model could steer future drug development in the right direction.
Expert Reactions and Future Prospects
Experts are optimistic about the potential impact of this new study on Parkinson’s research. Daniel Truong, MD, neurologist and medical director of the Truong Neuroscience Institute, underscored its importance:
“Mutations in the PINK1 gene have been linked to early-onset Parkinson’s disease. By resolving the structure of PINK1, researchers have provided deeper insights into its function and how its dysfunction can lead to neurodegeneration.” He also emphasised how this discovery could inform future treatments:
“Understanding the structural configuration of PINK1 will open avenues for developing targeted therapies aimed at modulating its activity. This could lead to interventions that enhance mitochondrial quality control mechanisms, potentially slowing or halting disease progression.”
Rocco DiPaola, MD, a neurologist specialising in movement disorders, viewed the study as a step forward in addressing hereditary forms of Parkinson’s, “It is important to continue to look for new ways to treat Parkinson’s disease, as current therapies have their limitations, primarily addressing dopaminergic systems.”
However, the road to treatment remains long, as Umer Akbar, MD, director of the Movement Disorder Centre at Hackensack University Medical Centre, noted, “Drug development is a long and complex process, and many promising drug candidates fail in clinical trials. However, this discovery undoubtedly removes a major obstacle and significantly increases the chances of developing effective therapies for Parkinson’s disease in the future.”
Conclusion
Researchers have made a significant advancement by revealing the structure of PINK1, opening new possibilities for Parkinson’s disease therapies.
This discovery provides valuable insight into how PINK1 functions, moving scientists closer to creating drugs that could enhance its activity and potentially slow or prevent disease progression. While more research is needed, the breakthrough offers new optimism in the search for effective treatments.