Walter and Eliza Hall Institute (WEHI) discovers PINK1’s structure, advancing Parkinson’s disease research by showing its mitochondrial interactions and potential for targeted therapies.

Walter and Eliza Hall Institute’s (WEHI) Parkinson’s Disease Research Centre has solved the mystery by determining the structure of human PINK1 when attached to the mitochondria.
The gene was first discovered over 20 years ago, PINK1 is a protein directly linked to Parkinson’s disease – the fastest-growing neurodegenerative condition in the world. The study findings were published in Science.

Parkinson’s disease is a serious condition that is difficult to diagnose. It may take years or sometimes decades to diagnose. 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.

Protecting Cells from Damage

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.

The study has visualized how it interacts with mitochondria to understand the cause of Parkinson’s disease. With the obtained structure, the gene can be modified and enhance its function. It can help with finding a treatment that could have a life-changing impact on people with Parkinson’s disease.

How PINK1 Removes Damaged Mitochondria

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 has not yet been 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.

Link between PINK1 and Parkinson’s Disease

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 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:

1. Structure of human PINK1 at a mitochondrial TOM-VDAC array – (https://www.science.org/doi/10.1126/science.adu6445)

Source-Medindia