Using the latest technology in genetic research, a Canadian-led study found a mutation in a gene called VPS35 causes late-onset Parkinson's disease. The researchers hope their discovery offers a new target for drugs to cure or stop the progress of this debilitating neurodegenerative condition.
You can read about the work of the international team in a paper published in the 15 July issue of The American Journal of Human Genetics, where lead author Carles Vilariño-Güell, from the University of British Columbia (UBC), and colleagues, describe how they used exome sequencing to screen for candidate gene mutations.
Exome sequencing analyzes just the "exome", or that part of the genome that expresses the genes responsible for making proteins and developing the human being after the fertilized egg stage. As it represents less than 2% of the total genome, sequencing just the exome is a more cost-effective way of screening for mutations behind diseases than looking at the whole genome.
Previous research has already identifed mutations in five genes that make people more susceptible to developing Parkinson's.
For this study, Vilariño-Güell, who is a post-doctoral research associate in the Department of Medical Genetics at UBC, and colleagues applied the novel technology to DNA samples from two cousins diagnosed with Parkinson's.
The cousins belong to a Swiss family where eleven members have developed the disease, and whose diagnostic characteristics the authors describe as "tremor-predominant dopa-responsive parkinsonism with a mean onset of 50.6 [plus or minus] 7.3 years".
Vilariño-Güell, who is also a member of the Centre for Molecular Medicine & Therapeutics (CMMT), told the press:
"We found one previously unidentified mutation was present in all the individuals in this family who had developed Parkinson's disease, but we did not see this mutation in any of the more than 3,000 healthy individuals whose DNA samples we studied."
The authors describe the mutation as an "aspartic-acid-to-asparagine mutation within vacuolar protein sorting 35 [VPS35]".
They also found the mutation in nine other people with Parkinson's: eight of whom came from three families with a history of Parkinson's, and the ninth had no family history of the disease. This second group of participants came from families spread around the world: from Tunisia to the US.
Vilariño-Güell said this further evidence was conclusive proof that the mutation caused the disease in these patients.
Senior author Matthew Farrer, a professor in the Department of Medical Genetics and Canada Excellence Research Chair in Neurogenetics and Translational Neuroscience at UBC, said their finding offers a new clue for understanding how Parkinson's develops.
VPS35 plays a key role in the retromer, the system that recycles proteins in neurons or brain cells. Faulty retromers have been implicated in Alzheimer's disease and Charcot-Marie-Tooth, a genetic disorder characterised by slowly progressive muscle weakness.
Farrer, who joined UBC from the Mayo Clinic in Florida, US, last year, said these findings are the first evidence that the retromer is also important for Parkinson's. He and his fellow authors conclude:
"Our study implicates disruption of VPS35 and retromer-mediated trans-membrane protein sorting, rescue, and recycling in the neurodegenerative process leading to PD [Parkinson's Disease]."
More than 10 million people worldwide are affected by Parkinson's disease: including 1 million in the US and more than 100,000 in Canada. There is currently no cure for the disease, and most treatments only deal with the symptoms, which include: trembling in the arms, legs, hands and face, stiffness in the limbs and the torso, poor balance and coordination and slowness of movement.
Funds from the Michael J. Fox Foundation, the Parkinson's Disease Foundation, and the Canada Excellence Research Chairs program helped pay for the study.
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