Researchers have solved a ten-year puzzle concerning a key protein associated to Parkinson’s disease, which could speed up the development of medicines for the incurable condition. Parkinson’s disease is a neurological condition that causes tremors, stiffness, and difficulty walking, balancing, and coordinating.
The study, which was published in Nature, created a ‘live action’ image of the protein PINK1 in fine molecular detail for the first time. The discovery reveals how the protein is triggered in the cell and how it starts the removal and replacement of damaged mitochondria.
When the protein isn’t working properly, it can deplete the energy supply of brain cells, leading them to malfunction and eventually die, as dopamine-producing cells do in Parkinson’s disease.
Amino acids are the ‘building blocks’ of proteins. Amino acids are required for the body to function properly. Some amino acids can only be obtained through the consumption of protein-rich meals.
Be a result, they are referred to as ‘necessary’ amino acids. The body produces ‘non-essential’ amino acids, and a healthy, balanced diet will help.
The discovery is the result of eight-year research and is the first thorough roadmap for the identification and development of therapeutic compounds that could help reduce or even stop Parkinson’s disease progression.
The multidisciplinary team at WEHI, led by PhD student Mr. Zhong Yan Gan and Professor David Komander, utilized cutting-edge cryo-electron microscopy capabilities and research to reach a breakthrough.
Although the majority of people with Parkinson’s disease develop the disease around the age of 60, about 5 to 10% of persons with Parkinson’s disease develop it before the age of 50. Parkinson’s disease is generally inherited, although not always, and some kinds have been linked to specific gene alterations.
One of the critical discoveries we made was that this protein forms a dimer or pair that is essential for switching on or activating the protein to perform its function. There are tens of thousands of papers on this protein family, but to visualize how this protein comes together and changes in the process of activation, is really a world-first.Mr. Gan
At a glance
For the first time, researchers at WEHI have shown the complete process that leads to the activation of PINK1, a protein that has been related to Parkinson’s disease.
The researchers were able to examine every step of the process, from the beginning of PINK1 production to how abnormalities in the protein cause Parkinson’s disease.
The researchers’ improved understanding of the molecular foundation of Parkinson’s disease has the potential to lead to new treatments.
Turning the switch off
Parkinson’s disease is a neurological disease that develops as dopamine-producing cells in the brain die. Parkinson’s disease affects more than 10 million individuals globally, including more than 80,000 Australians.
There are currently no licensed treatments that can slow or stop Parkinson’s disease progression, with present therapies only able to treat and mitigate symptoms.
The findings provide an unparalleled perspective of a protein called PINK1, which is known to play a vital role in early-onset Parkinson’s disease, according to PhD student and first author Zhong Yan Gan.
“Many papers from laboratories around the world including ours have captured snapshots of the PINK1 protein. However, the differences in these snapshots has in some ways fuelled confusion about the protein and its structure,” Mr. Gan said.
“What we have been able to do is to take a series of snapshots of the protein ourselves and stitch them together to make a ‘live action’ movie that reveals the entire activation process of PINK1. We were then able to reconcile why all these previous structural images were different they were snapshots taken at different moments in time as this protein was activated to perform its function in the cell.”
PINK1 preserves the cell by marking damaged mitochondria, the cell’s energy powerhouse, for destruction and recycling. When PINK1 or other pathway components are defective, the cell is deprived of energy by blocking the recycling and replacement of damaged mitochondria with healthy ones.
“One of the critical discoveries we made was that this protein forms a dimer or pair that is essential for switching on or activating the protein to perform its function. There are tens of thousands of papers on this protein family, but to visualize how this protein comes together and changes in the process of activation, is really a world-first,” Mr. Gan said.
Drug discovery potential
Professor Komander claims that his team’s discovery has prepared the door for the development of therapeutics that ‘turn on’ PINK1 to treat Parkinson’s disease.
“There are currently no disease-modifying drugs available for Parkinson’s disease that is no drugs that can slow the progression of the disease or halt its development,” Professor Komander said.
In some cases of Parkinson’s disease, malfunctions in PINK1 or other elements of the mitochondrial repair pathway are thought to be a crucial feature. This knowledge is especially important for a subset of young people who develop Parkinson’s disease in their 20s, 30s, and 40s as a result of genetic PINK1 mutations.
According to Professor Komander, the discovery will open up new avenues for treating Parkinson’s disease through this channel.
“Biotech and pharmaceutical companies are already looking at this protein and this pathway as a therapeutic target for Parkinson’s disease, but they have been flying a bit blind. I think they’ll be really excited to see this incredible new structural information that our team has been able to produce using cryo-EM. I’m really proud of this work and where it may lead,” he said.
Parkinson’s disease research at WEHI is supported by the Australian National Health and Medical Research Council, The Michael J. Fox Foundation, Shake-It-Up Australia, a CSL Centenary Fellowship, Bodhi Foundation, Australian Government Research Training Program Scholarship, and the Victorian Government, and benefits from generous philanthropic support, including Leon Davis AO and Annette Davis.
The cryo-EM work for this study was performed at the Bio21 Advanced Microscopy Facility and was supported by the WEHI Information Technology Services and the WEHI Research Computing Platform.