As recently as 15 years ago, the idea of Parkinson`s disease having a genetic influence was considered a heresy. “If you read any medical or neurology textbook, it would say Parkinson’s disease is a sporadic disorder. There is no heritable component,” says Dr. Matthew Farrer, Canada Excellence Research Chair in Neurogenetics and Translational Neuroscience at the University of British Columbia (UBC).
That viewpoint is changing. Today, close to 20 regions of the human genome have been identified as contributing to Parkinson’s. “Within seven of those regions, mutations in specific genes have been shown to segregate with disease down the family line, and consequently are predictive of you manifesting the disease,” says Farrer. “We all have something in our genome that predisposes us to one disease or another. Parkinson’s is just another example of that.”
A molecular geneticist and neuroscientist with a special interest in Parkinson’s and Lewy body dementia, Farrer invites individuals and families with a history of Parkinson’s to donate blood and provide basic clinical and family history information. He then maps gene mutations, most recently using advanced DNA sequencing technology that has made the process less laborious and more affordable.
This work is paying off. In one of his most recent discoveries, by comparing cousins with Parkinson’s from a single large family, Farrer and colleagues found a mutation in vesicular protein sorting 35 (VPS35), a protein involved in recycling membrane-associated proteins within cells.
What’s different about the VPS35 mutation is that it is not simply a risk factor. “This is a very specific cause of Parkinson’s,” says Farrer. “It’s a single nucleotide change that leads to a single amino change in a single protein. Family members who inherit this mutation develop the complex syndrome we call Parkinson’s. It’s an amazing discovery that gives us firm ground to build on.” The average age of onset for VPS35-parkinsonism is about 55, compared to 60 for most forms of late-onset Parkinson’s.
The research, published in the American Journal of Human Genetics in July 2011, was validated by publication, in the same issue, of an identical finding by a separate group of researchers, using totally different families from another part of the world.
However, Farrer notes, “Finding a gene is just the beginning. What’s more important is taking that information and translating it into something useful.” So, Farrer and his team of neuroscientists are introducing mutant VPS35 protein into organisms to determine exactly what it does in brain cells. They want to get to the core reason why neurons in the area of the brain, known as the substantia nigra, die in Parkinson’s. “The leads we get translate into tests and models that pharmaceutical companies use for drug screening,” say Farrer.
Both individually and as a network, the major genetic discoveries in Parkinson’s – alpha-synuclein, DJ-1, EIF4G1, LRRK2, Parkin, PINK1 and now, VPS35 – are providing targets for new therapies that hold the promise of addressing the underlying causes of the disease not just the symptoms. “That’s the wonderful thing about molecular genetics in Parkinson’s, it suggests we might halt, in effect, prevent this condition, and provides the tools to accomplish it,” says Farrer.
For more information on the cutting-edge research undertaken at the Centre for Applied Neurogenetics at the University of British Columbia, visit www.can.ubc.ca.