The Structure of Key Proteins in Parkinson's Disease Solved

Australian researchers have recently solved a multi-year mystery about Parkinson's disease. They solved the structure of a key protein that is expected to rapidly treat this incurable disease. The findings appear in Nature.

For the first time, the researchers took a "live" shot of a protein called PINK1. The findings explain how this protein is activated in cells, thereby initiating the clearance and replacement of damaged mitochondria. When this protein does not work properly, it causes brain cells to lack energy, resulting in their dysfunction, which can lead to brain cell death in the long term.

Discovery is a new achievement of an eight-year project that provides the first detailed blueprint for the discovery and development of therapeutic agents to slow the development of Parkinson's disease.

Parkinson's disease is a progressive neurodegenerative disease caused by the death of dopamine-producing cells in the brain. More than 10 million people worldwide suffer from Parkinson's disease. There are no drugs that can slow or stop the progression of Parkinson's disease, and existing treatment options can only treat and relieve symptoms.

Zhong Yan Gan, first author of the study, stated that this study provides an unprecedented perspective to better understand the PINK1 protein, which plays a key role in early-onset Parkinson's disease." Many papers in laboratories around the world, including ours, have captured snapshots of PINK1 protein. However, the differences in these snapshots somewhat exacerbate the confusion about proteins and their structures," he says.

"What we do is take snapshots of a series of proteins and then stitch them together to make a 'real world' film, thereby revealing the activation process of PINK1. We are then able to explain why these previous structural images are different—because they are taken at different times, and this protein is activated to perform its function in the cell."

PINK1 labels damaged mitochondria, allowing them to be destroyed and recycled, thereby protecting cells. When PINK1 or other components of this pathway are defective, it prevents the recovery and replacement of damaged mitochondria, thereby depriving the cell of energy.

Zhong Yan Gan said: "One of our important findings is that PINK1 forms a dimer, which is essential to initiate or activate proteins to perform their functions. There are tens of thousands of papers on this protein family, but it is indeed the first time in the world to observe how proteins cluster together and how they change during activation.”

Professor Komander, corresponding author of this article, said these results pave the way for the development of therapeutic agents that "open" PINK1 to treat Parkinson's disease. There are no drugs for Parkinson's disease, that is, no drugs can slow or stop the progression of the disease. "

Failure of PINK1 or other components in the pathway is considered a key feature in some cases of Parkinson's disease. At the same time, this information is particularly important for the young population who develop Parkinson's disease due to inherited mutations in PINK1. Professor Komander said the discovery will bring new opportunities for the treatment of Parkinson's disease.

Dr. Alisa Glukhova of the Walter and Eliza Hall Institute for Medical Research said the reason why the findings were possible was due to the new cryo-EM equipment purchased jointly by the WEHI and Bio21 institutes, as well as the structural biologists recruited by WEHI who were familiar with the technology.

Dr. Glukhova said: "For the first time, we used cryo-EM at WEHI to solve small protein structures like PINK1. This revolutionary technology has only been introduced in the past five years, and this work has become possible because WEHI has invested in the purchase of equipment and has the expertise required to make full use of this technology. A good example of how innovative technologies can really drive research and bring transformative discoveries."