Scientists have identified the structure of a key enzyme – called PINK1 – that when mutated can cause Parkinson’s disease.
The research team from the MRC Protein Phosphorylation and Ubiquitylation Unit (MRC PPU) and the University of Dundee said that solving the 3D structure and inner workings of the PINK1 enzyme could help researchers to develop new drugs against the disease.
Previous advances in genetics identified that inherited mutations in the PINK1 gene are the second most frequent cause of early-onset Parkinson’s disease. Parkinson’s is a progressive degenerative brain disorder which to date remains incurable.
In this new research, published in the journal eLife, the scientists revealed the structure of PINK1, isolated from the model organism Tribolium castaneum (red flour beetle). They found that PINK1 has unique control elements not found in other enzymes of this class that explain how it targets two key proteins ubiquitin and Parkin to exert its protective role in the brain.
Dr Miratul Muqit, from the MRC-PPU, who co-led the research team, said: “Solving the structure and workings of PINK1 gives us crucial insights in to how it exerts a protective role in Parkinson’s. 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.”
PINK1 encodes a special class of enzyme known as a kinase that plays a critical role in protecting brain cells against stress. In patients harbouring PINK1 mutations, this protective effect is lost leading to the degeneration of cells controlling movement that account for Parkinson’s symptoms.
Previous work had indicated that the main role of the PINK1 enzyme is to sense damage to the energy centres of cells known as mitochondria and then switch on a protective pathway involving the targeting of two key proteins, ubiquitin and Parkin, to reduce the damage. But how this occurred was unknown.
Professor Daan van Aalten, from the School of Life Sciences at the University of Dundee, who co-led the research team, said, “There has been great interest in directly targeting PINK1 as a potential therapy but without knowledge on the structure of the enzyme, this posed a major barrier. Our work now provides a framework to undertake future studies directed at finding new drug like molecules that can target and activate PINK1. This provides detailed insights into how mutations carried by hundreds of Parkinson’s patients worldwide interrupt the function of the enzyme.”
Professor Dario Alessi, Director of the MRC PPU, commented: “This is a wonderful achievement and has been a very difficult project that has taken over eight years of painstaking research. Many researchers would have given up long ago. This work illustrates the importance of persistence and collaboration that is required to solve the most important problems in medical research. Dr Muqit was a key member of the team that discovered PINK1 in 2003 and has made many valuable contributions to our understanding of PINK1 in Parkinson’s disease.”
Dr Nathan Richardson, MRC Head of Molecular and Cellular Medicine, said, “Discovering the fundamental structure of this protein is vital for understanding its cellular function and paves the way for the development of drugs to combat forms of early-onset Parkinson’s disease. This advance will also help reveal the molecular basis of genetic mutations in Parkinson’s disease, illustrating the merit of long term support for underpinning biomedical research.”
The research was funded by the Wellcome Trust, MRC, Biotechnology and Biological Sciences Research Council, and Parkinson’s UK, including the Parkinson’s UK branches of Fife and Ayrshire.