Scientists solve decades-long Parkinson’s mystery

WEHI researchers have made a huge leap forward in the fight against Parkinson’s disease, solving a decades-long mystery that paves the way for the development of new drugs to treat the condition.

First discovered over 20 years ago, PINK1 is a protein directly linked to Parkinson’s disease—the fastest growing neurodegenerative condition in the world. Until now, no one had seen what human PINK1 looks like, how PINK1 attaches to the surface of damaged mitochondria, or how it is switched on.

In a major breakthrough, researchers at the WEHI Parkinson’s Disease Research Center have determined the first ever structure of human PINK1 bound to mitochondria, in findings published in Science.

The study, “Structure of human PINK1 at a mitochondrial TOM-VDAC array,” could help find new treatments for the condition that currently has no cure or drug to stop its progression.

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 health care 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 Signaling 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 Center.

“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 of 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 hope 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.