Over the last 10 years as a doctor specialising in Parkinson’s disease, I have been asked by my patients many times whether a cure was in sight. I used to struggle to answer that question with anything but ambivalence given the long list of failures of clinical trials in Parkinson’s.
However, recent advances made in the identification of genes linked to Parkinson’s now provide much more optimism that better treatments are on the horizon. Understanding how faults in these genes cause the condition has heralded a golden age of discovery, revealing the cellular highways that go wrong in the brain cells of Parkinson’s patients.
A major step forwards was achieved in 2004 through the discovery of a gene called PINK1 in heritable forms of Parkinson’s. PINK1 encodes a special class of enzyme known as a “kinase”. At that time, abnormalities in kinases had been found in many types of cancer and this had led to the first designer drugs targeting the disease.
However, the role of kinase pathways in Parkinson’s was an entirely new concept and nothing was known about it. Building on this genetic discovery, our laboratory based at the MRC Protein Phosphorylation and Ubiquitylation Unit in Dundee, together with others around the world, has been studying PINK1 to understand its function and identify the specific pathways out of the hundreds of thousands of pathways in a brain cell that it might control.
Through a series of discoveries from our laboratory and others, it has emerged that PINK1 acts as a molecular “switch” to protect the brain against developing Parkinson’s. At the microscopic level, PINK1 is a major defence protein that keeps the energy-producing centres of cells known as “mitochondria” in a healthy state. The implications of this research is that drugs targeting PINK1 to switch on its activity could slow down the disease in patients for the first time.
A thrilling breakthrough
To accelerate the development of such drugs, we formed a collaboration with the laboratory of Professor Daan van Aalten at the University of Dundee to determine the atomic structure or “molecular roadmap” of the PINK1 enzyme. This process involves a series of challenging steps that first requires engineering the PINK1 enzyme in a test tube. The enzyme is then made into ordered crystals which are exposed to high energy X-rays that cause them to scatter in a unique pattern. Analysis of this pattern allows the arrangement of atoms inside the crystal to be calculated, thereby solving the biomolecular structure.
And after eight years of research, and in the midst of competition worldwide, we have solved the structure of PINK1, revealing the inner workings of the enzyme. Our structure showed that PINK1 is unique from the other 500 members of the kinase family and explains precisely how it is able to engage with its targets to catalyse reactions in the cells.
Seeing the structure of PINK1 for the first time was a thrilling moment and testament to the dedication of our team of scientists, who simply never gave up on their goal. But more importantly, it has major implications for patients suffering from Parkinson’s.
Knowing what PINK1 looks like at this level now enables us to explain to patients who harbour faults in their PINK1 gene why they have developed Parkinson’s. This will aid in the diagnosis of Parkinson’s, providing an explanation for how changes in the PINK1 gene may affect the structure.
In my clinical experience, this is also tremendously important as many patients develop Parkinson’s at a young age and often ask, why me? At the same time, this knowledge will also boost our ability to develop designer drugs against the disease.
There is no doubt that as a consultant working with Parkinson’s patients I will still have many tough conversations. But this advance brings us a step closer to my belief that I will witness something in my lifetime that will change how I and other neurologists treat patients with Parkinson’s.