Researchers have produced the first “live action” view of a protein believed to play a key role in the development of Parkinson’s disease — a discovery that may accelerate the arrival of badly needed therapeutics for the incurable disease.
The research, published in the journal Nature, spanned eight years and culminated in an enhanced understanding of the creation, activation and behaviour of PINK1, the protein responsible for initiating the removal and replacement of damaged mitochondria within cells. When this protein malfunctions, vital dopamine-producing cells in the brain become starved of energy and eventually die in a process believed to give rise to Parkinson’s disease.
“Many papers from laboratories around the world — including ours — have captured snapshots of the PINK1 protein, said Zhong Yan Gan, one of the leaders of the study and a PhD student at the Walter and Eliza Hall Institute of Medical Research (WEHI) in Australia. “However, the differences in these snapshots has in some ways fuelled confusion about the protein and its structure.
“What we have been able to do is to take a series of snapshots of the protein ourselves and stitch them together to make a ‘live action’ movie that reveals the entire activation process of PINK1,” he said. “We were then able to reconcile why all these previous structural images were different — they were snapshots taken at different moments in time as this protein was activated to perform its function in the cell.”
Parkinson’s disease is a brain disorder that occurs when clusters of nerve cells (or neurons) controlling the body’s movement die or malfunction, resulting in a decrease in the production of dopamine. In addition to producing the motor control issues commonly seen in patients, the progressive disease also damages the nerve endings that produce norepinephrine — a messenger in the nervous system — likely accounting for non-motor symptoms such as fatigue and digestive issues. There are currently no approved drugs that can slow or stop the progression of the disease, with current therapies only able to address and alleviate symptoms.
By shedding light on the role PINK1 plays in cellular death and the early onset of the disease, researchers hope that will soon change.
“One of the critical discoveries we made was that this protein forms a dimer — or pair — that is essential for switching on or activating the protein to perform its function,” Gan said. “There are tens of thousands of papers on this protein family, but to visualize how this protein comes together and changes in the process of activation, is really a world-first.”
This knowledge may eventually open the door to new therapeutics that restore the ability of faulty PINK1 proteins to repair malfunctioning cells. “Biotech and pharmaceutical companies are already looking at this protein and this pathway as a therapeutic target for Parkinson’s disease but they have been flying a bit blind,” said David Kommander, one of the leaders of the study and a professor at WEHI in Australia. “I think they’ll be really excited to see this incredible new structural information that our team has been able to produce using cryo-EM. I’m really proud of this work and where it may lead.”
There are more than 100,000 Canadians living with Parkinson’s today and roughly 6,600 new diagnoses every year. Typically confirmed around the age of 65 when symptoms become undeniable, the associated costs of managing the disease are more than $1.2-billion in Canada. Monthly medications alone cost the typical Canadian patient more than $1,000 per month.
Dave Yasvinski is a writer with Healthing.ca
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