WEHI researchers have solved a decades-long mystery by determining the structure of human PINK1, a key protein linked to Parkinson’s disease. This breakthrough, published in Science, could accelerate the search for new drugs to slow or stop Parkinson’s progression.
WEHI researchers have made a significant breakthrough in the fight against Parkinson’s disease, resolving a decades-old mystery and opening the door for new drug development.
PINK1, a protein directly linked to Parkinson’s, the world’s fastest-growing neurodegenerative disease, was first discovered over 20 years ago. However, until now, its structure, how it attaches to damaged mitochondria, and the mechanism that activates it remained unknown.
Now, for the first time, researchers at the WEHI Parkinson’s Disease Research Centre have mapped the structure of human PINK1 bound to mitochondria. Their findings, published in Science, could pave the way for new treatments for Parkinson’s, a condition that currently has no cure or disease-modifying drugs.
At a glance
- In a world-first, WEHI researchers have discovered what human PINK1 looks like and how it is activated.
- PINK1 is a protein linked to Parkinson’s disease, the second most common neurodegenerative disease after Alzheimer’s. There is no cure for Parkinson’s.
- This discovery, published in Science, is a huge leap forward in the fight against Parkinson’s with the hope that it will accelerate the search for a drug to stop the condition.
Parkinson’s disease is insidious, often taking years, sometimes decades to diagnose. Often associated with tremors, there are close to 40 symptoms including cognitive impairment, speech issues, body temperature regulation, and vision problems.
In Australia, over 200,000 people live with Parkinson’s and between 10% and 20% have Young Onset Parkinson’s Disease – meaning they are diagnosed under the age of fifty. The impact of Parkinson’s on the Australian economy and healthcare systems is estimated to be over $10 billion each year.
Breakthrough after decades of research
Mitochondria produce energy at a cellular level in all living things, and cells that require a lot of energy can contain hundreds or thousands of mitochondria. The PARK6 gene encodes the PINK1 protein, which supports cell survival by detecting damaged mitochondria and tagging them for removal.
In a healthy person, when mitochondria are damaged, PINK1 gathers on mitochondrial membranes and signals through a small protein called ubiquitin, that the broken mitochondria need to be removed. The PINK1 ubiquitin signal is unique to damaged mitochondria, and when PINK1 is mutated in patients, broken mitochondria accumulate in cells.
Although PINK1 has been linked to Parkinson’s, and in particular Young Onset Parkinson’s Disease, researchers had been unable to visualize it and did not understand how it attaches to mitochondria and is switched on.
Corresponding author on the study and head of WEHI’s Ubiquitin Signalling Division, Professor David Komander, said years of work by his team have unlocked the mystery of what human PINK1 looks like, and how it assembles on mitochondria to be switched on.
“This is a significant milestone for research into Parkinson’s. It is incredible to finally see PINK1 and understand how it binds to mitochondria,” said Prof Komander, who is a laboratory head in the WEHI Parkinson’s Disease Research Centre.
“Our structure reveals many new ways to change PINK1, essentially switching it on, which will be life-changing for people with Parkinson’s.”
Hope for future treatments
Lead author on the study, WEHI senior researcher Dr Sylvie Callegari, said PINK1 works in four distinct steps, with the first two steps not being seen before.
First, PINK1 senses mitochondrial damage. Then it attaches to damaged mitochondria. Once attached it tags ubiquitin, which then links to a protein called Parkin so that the damaged mitochondria can be recycled.
“This is the first time we’ve seen human PINK1 docked to the surface of damaged mitochondria and it has uncovered a remarkable array of proteins that act as the docking site. We also saw, for the first time, how mutations present in people with Parkinson’s disease affect human PINK1,” said Dr Callegari.
The idea of using PINK1 as a target for potential drug therapies has long been touted but not yet achieved because the structure of PINK1 and how it attaches to damaged mitochondria were unknown.
The research team hopes to use the knowledge to find a drug to slow or stop Parkinson’s in people with a PINK1 mutation.
The link between PINK1 and Parkinson’s
One of the hallmarks of Parkinson’s is the death of brain cells. Around 50 million cells die and are replaced in the human body every minute. But unlike other cells in the body, when brain cells die, the rate at which they are replaced is extremely low.
When mitochondria are damaged, they stop making energy and release toxins into the cell. In a healthy person, the damaged cells are disposed of in a process called mitophagy.
In a person with Parkinson’s and a PINK1 mutation, the mitophagy process no longer functions correctly and toxins accumulate in the cell, eventually killing it. Brain cells need a lot of energy and are especially sensitive to this damage.
Reference: “Structure of human PINK1 at a mitochondrial TOM-VDAC array” by Sylvie Callegari, Nicholas S. Kirk, Zhong Yan Gan, Toby Dite, Simon A. Cobbold, Andrew Leis, Laura F. Dagley, Alisa Glukhova and David Komander, 13 March 2025, Science.
DOI: 10.1126/science.adu6445
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