A New Zealand-led study, backed by Hollywood star Michael J Fox's world-renowned charity, has gained fresh insights into one gene's crucial role in Parkinson's disease.
Parkinson's is a progressive neurodegenerative condition caused by a lack of dopamine in the brain, resulting in slow and awkward movement.
Despite decades of research, and its impact on one in 500 New Zealanders and millions more around the world, the disease remains a medical mystery.
Doctors don't yet know why most people develop it and for those diagnosed, there's no cure.
Now, a team of scientists believe they've found a promising new lead in a genetic mutation that poses one of the biggest risk factors for the disease.
The specific gene involved is called glucocerebrosidase beta acid, or GBA.
Studies have already shown how GBA mutations hamper an enzyme that helps clean out degraded or excess cell parts, before they can build up to cause the damage seen in Parkinson's disease.
Associate Professor Justin O'Sullivan, of the University of Auckland-based Liggins Institute, said his team had discovered the specific components of GBA which play a big part in regulating and delaying the disease's onset.
"The question we are asking is why do some people with GBA mutations develop Parkinson's and others do not?" said O'Sullivan, who has been working with researchers from the University of Otago and Australia's Garvan Institute of Medical Research.
The investigation led them to the non-coding parts of the GBA gene that were once thought of as "junk DNA".
Scientists such as O'Sullivan have since demonstrated that, far from being useless, these DNA sequences can act as switches that regulate the action of genes, among other things.
In GBA's non-coding areas, the team screened 128 sites to find that, where the gene happened to have a specific combination of three short non-coding DNA sequences, the onset of Parkinson's could be delayed by five years.
They also identified six other non-coding regions that act as switches to control how the GBA gene was turned on or off in the movement and cognitive centres of the brain: the substantia, nigra and cortex.
The team has now created a map showing how such switches affect other genes – in addition to GBA - throughout the human body.
"Traditionally, Parkinson's has been seen as a disease of the brain," O'Sullivan said.
"We suggest that the regulation of GBA throughout the body is important in the development of the disease and that there is a network effect through how the switches control the GBA gene and other genes."
The new information not only meant there was now a way to improve the screening of candidates for medical therapies, it also opened up new ground to explore ways to prevent, delay and treat Parkinson's, through gene and drug therapies.
"Because we know the genes and pathways that are affected by these subtle genetic changes, we might also be able to better target the processes that are changing – and much earlier in life – in people who have these changes and are at risk of developing Parkinson's disease," O'Sullivan explained.
"Imagine the impact on people if we could delay disease onset by 10 years, or slow progression.
"But there is a lot of work to do to achieve this and it won't be done by one research group.
"What we are trying to do now is to determine how the changes we identified connect to the other genetic changes that are known to be associated with Parkinson's.
"It's a jigsaw puzzle we think we are making some headway on. Hopefully the picture turns out to be inspirational."
O'Sullivan and his colleagues have already applied their unique 3D genome-mapping tool, which relies heavily on computational analysis, to illuminate a previously unknown genetic driver in type 1 diabetes, and help explain why clusters of certain diseases and characteristics often go hand-in-hand in the same person.
The GBA work was funded by the Michael J Fox Foundation for Parkinson's Research and the Silverstein Foundation for Parkinson's with GBA.
Fox, best known for his roles in Back To The Future, Doc Hollywood and Spin City, partly retired from acting soon after going public with his own battle against the disease 20 years ago.
He has since gone on to become one of the world's best-known advocates for research towards finding a cure.
O'Sullivan said the funding supported three researchers in the team, and also enabled a collaboration with the Garvan Institute.
"More than this, it also provided us with access to the MJFF GBA consortium conference calls, held at 3am New Zealand time, where researchers present and discuss their results as they are generated before publication," he said.
"Without a doubt, the feedback and insights from these live forums are worth getting up for and have helped immensely."
The study has been published in the journal Movement Disorders.
• Parkinson's is a progressive neurodegenerative condition caused by insufficient quantities of dopamine - a chemical in the brain. Parkinson's has both motor and non-motor symptoms, and while it cannot be cured, it can be treated.
• As Parkinson's is a progressive condition, it can often take many years to develop and has little effect on life expectancy.
• About one in 500 people have the condition. It becomes more common with older age groups, and it is believed 1 per cent of people above the age of 60 have Parkinson's.
• While the cause of the majority cases are unknown, about 10 per cent of people with Parkinson's are thought to have a genetic form of the condition.