The study, titled “Structure of PINK1 and mechanisms of Parkinson’s disease associated mutations,” was published in the journal eLIFE.
Mutations in the PINK1 gene, which codes for an enzyme that protects brain cells against stress, lead to the development of Parkinson’s. When the mutation renders the enzyme ineffective, the protective effect is no longer in place, which causes the degeneration of cells that control movement, leading to the movement symptoms that are observed in Parkinson’s disease patients.
Studies have shown that the PINK1 enzyme causes the activation of pathways that result in the production of the proteins ubiquitin and parkin, which work to protect brain cells. But the method by which PINK1 conducts this function has been unknown. This led researchers to solve the three-dimensional structure of PINK1 using the enzyme found in the organism Tribolium castaneum.
“Solving the structure and workings of PINK1 gives us crucial insights in to how it exerts a protective role in Parkinson’s,” Dr. Miratul Muqit, a neurologist at the University of Dundee and co-lead of this research study, said in a press release.
“That knowledge can lead to the development of new drugs which could be designed to ‘switch on’ PINK1 to the benefit of patients with Parkinson’s,” Muqit said.
The structure of the PINK1 enzyme has three loop-style insertions that previously had an unknown function. Researchers have demonstrated that the third loop insertion, which is modified through a mechanism called phosphorylation at a specific site, leads to the formation of a bowl shape, which is essential as a binding site for the ubiquitin protein.
The researchers also describe an interesting structural element held by a loop that is necessary for the activity of PINK1. These results demonstrate how mutations that affect the kinase domain within the bowl of the enzyme can lead to a loss of PINK1 function.
“There has been great interest in directly targeting PINK1 as a potential therapy, but without knowledge on the structure of the enzyme, this has posed a major barrier,” said Dr. Dan van Aalten, co-investigator of the study and professor in the Division of Gene Regulation and Expression in the School of Life Sciences at the University of Dundee.
“Our work now provides a framework to undertake future studies directed at finding new drug-like molecules that can target and activate PINK1,” van Aalten said. “This provides detailed insights into how mutations carried by hundreds of Parkinson’s patients worldwide interrupt the function of the enzyme.”
Prof. David Dexter, deputy director of research at Parkinson’s UK, said scientists funded by the organization identified the PINK1 gene as a “key player” in 2004.
“Drugs that can switch the PINK1/parkin pathway back on may be able to slow, stop or even reverse nerve cell death, not only in people who have these rare inherited forms of the condition, but also those with non-inherited Parkinson’s,” he said.
“This research, for the first time, gives us a view of what the PINK1 protein looks like and how changes in the gene can prevent the PINK1 protein working properly.
“This knowledge is vital for developing drugs that can switch PINK1 back on, which has the potential to slow or even stop the progression of the condition, something current treatments are unable to do,” Dexter added.
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