Scientists make ‘life-changing' discovery over protein linked with Parkinson's
Experts have known for several decades that the PINK1 protein is 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 inside of cells, or how it is activated.
But scientists have now discovered how the mutation switches on and can start using this knowledge to find a way to switch it off and slow the progression of the condition down.
Researchers at the Walter and Eliza Hall Institute, Parkinson's Disease Research Centre, in Australia, have solved the decades-long mystery.
The findings published in the Journal Science reveal for the first time ever the structure of PINK1 and how it binds to mitochondria – the powerhouse of a cell – and stops it functioning properly.
Parkinson's disease can take 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.
The neurological condition affects around 153,000 Britons. There is currently no cure for Parkinson's, although medicine, physiotherapy and surgery can help manage symptoms.
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.
In particular, PINK1 has been linked to young-onset Parkinson's Disease, which affects people under the age of 50. Despite the known link, researchers have previously been unable to visualise the protein or how it works.
'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 Professor David Komander, corresponding author on the study.
'Our structure reveals many new ways to change PINK1, essentially switching it on, which will be life-changing for people with Parkinson's,' he added.
Lead author on the study, Dr Sylvie Callegari, said PINK1 works in four distinct steps, with the first two steps not having been seen before.
First, PINK1 senses mitochondrial damage. Then it attaches to damaged mitochondria. Once attached, it 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.
Researchers in the UK also believe the discovery could lead to better drug design.
Consultant neurologist Dr Richard Ellis said: 'It is a crucial step towards understanding the impact of PINK1 in Parkinson's disease. These observations may hopefully create new opportunities for developing novel strategies for slowing the progression of Parkinson's disease.'
Dr Zhi Yao, research scientist, Life Arc, said: 'A robust understanding of these aspects could present a significant opportunity for accelerating drug discovery for Parkinson's disease and potentially other neurodegenerative conditions too.'
Becky Jones, research communications manager, at Parkinson's UK, said: 'Changes in the PINK1 have long been linked to Parkinson's, and a specific mutation in the gene that contains the instructions for making the protein are known to cause a rare inherited form of the condition.
'It's encouraging to see this research, which will help us understand how changes in PINK1 might be causing damage to dopamine-producing brain cells in people with Parkinson's.
'This knowledge unlocks future avenues for better drug design and discovery of a treatment that could slow or even stop Parkinson's progression. This is vital, as despite it being the fastest growing neurological condition in the world, we don't yet have any drug treatments that can do this.'
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