An illustration of a protein complex, one coloured pink and the other grey, on a black background
PINK1 (pink) docked to the TOM complex (grey) of the mitochondrial membrane. Credit: WEHI
In an important win for people living with Parkinson’s, a new study has finally determined the structure of a protein linked to an early-onset form of the disease.
The work shows how a protein, PINK1, attaches to the surface of damaged mitochondria, a new insight which could help researchers find a drug to slow or stop Parkinson’s in people with a PINK1 mutation.
“This is a significant milestone for research into Parkinson’s,” says Professor David Komander, corresponding author of the study in the journal Science and laboratory head in the WEHI Parkinson’s Disease Research Centre, Australia.
“It is incredible to finally see PINK1 and understand how it binds to mitochondria.
“Our structure reveals many new ways to change PINK1, essentially switching it on, which will be life-changing for people with Parkinson’s.”
Parkinson’s disease is the second most common neurodegenerative disease in the world behind Alzheimer’s. By 2050, it is projected that 25.2 million people will be living with the disease, posing a significant public health challenge.
It is associated with more than 40 symptoms, including tremors, cognitive impairment, speech issues, body temperature regulation and vision problems.
While Parkinson’s typically effects people over the age of 60, a subset of patients are diagnosed before the age of 50 with young-onset Parkinson’s (YOP).
PINK1 gathers on the surface of mitochondria, the energy-producing organelles inside cells.
When mitochondria are damaged, they stop making energy and release toxins into the cell. In a healthy person, PINK1 tags these damaged mitochondria with a protein (ubiquitin) which signals to the cell that they need to be removed.
But this doesn’t happen in a person with YOP whose PINK1 is mutated.
Instead, damaged mitochondria and toxins accumulate, eventually killing the cells. And brain cells, which need a lot of energy, are especially sensitive to this damage.
Until now, researchers had been unable to visualise PINK1 and did not understand how it attaches to mitochondria and is switched on, limiting their ability to develop drugs to restore its function.
“This is the first time we’ve seen human PINK1 docked to the surface of damaged mitochondria,” says lead author of the study and WEHI senior researcher, Dr Sylvie Callegari.
“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.”
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