Advances in Parkinson’s: Rethinking a challenging disease

By Amanda Strong, Medical Writer, Montreal, QC

This article was scheduled to be published in June in Dimensions, the online magazine of the National Research Council of Canada.

Recent progress in our understanding of Parkinson’s disease is challenging long-established beliefs and may even pave the way for a cure.

Not long ago, Parkinson’s disease was a bit of a mystery. Although scientists knew it was a neurodegenerative disease linked with a lack of the neurotransmitter, dopamine, no one really understood what triggered it or how it progressed.

In recent years, many clues have been found, leading to changes in how we think about Parkinson’s — from the core cause to the early warning signs to how the disease spreads in the brain. And while the mystery of Parkinson’s is far from solved, this “re-thinking” is opening new avenues for prevention and treatment.

Genetic mutations provide exciting clues
One of the critical turning points in our understanding came in 1997, when researchers discovered an abnormal gene that appeared to be responsible for early-onset Parkinson’s. The discovery gave birth to a whole new direction in Parkinson’s research.

“Fifteen years ago, people were saying that genetics is not involved in Parkinson’s,” says Dr. Edward Fon, Chair of the Scientific Advisory Board of Parkinson Society Canada and Director of the McGill Parkinson Program. “So it’s a huge paradigm shift.”

Since then, researchers have identified mutations in seven genes that are directly linked to developing Parkinson’s. Genetic variability in at least five more genes is associated with an increased risk of developing the disease. Although pathogenic mutations (those that cause disease) account for only a small percentage of all Parkinson’s cases, they provide clues to our understanding of the disease, as well as targets for potential treatments.

“We’re tantalizingly close to a therapeutic and that is the biggest prize of all,” says Dr. Matt Farrer, Canada Excellence Research Chair in Neurogenetics and Translational Neuroscience at the University of British Columbia (UBC).

For example, the most common mutation involves a protein called LRRK2, which may become overactive. By blocking the protein’s function, some researchers believe they can protect patients against the neurodegeneration associated with Parkinson’s.

Identifying patients at risk
Another thing that has become clear in recent years is that Parkinson’s is not just a dopamine disease. Although the debilitating symptoms (such as trembling and rigidity) appear to be caused by the death of dopamine-releasing cells in a particular region of the brain, scientists now believe that changes are happening in other areas of the brain long before these symptoms appear.

Brain imaging studies of patients who are at high risk of developing Parkinson’s due to family history or ancestry seem to support this theory. But short of routine brain scans, how can doctors identify people who may have Parkinson’s but don’t yet display any visible symptoms?

It turns out that many patients with Parkinson’s have a medical history of loss of smell, abnormal REM (rapid eye movement) sleep, excessive sleepiness, chronic constipation, or other conditions.

“Many of these non-motor manifestations of the disease occur years or decades before, and so it may be a way to identify patients before it’s too late,” says Dr. Fon.

At the McGill University Health Centre in Montréal, Dr. Ron Postuma is looking at these connections, with funding from Parkinson Society Canada. So far, one of the most promising appears to be REM sleep behaviour disorder (RBD). About a third of Parkinson’s patients have a history of RBD. Studies have shown that after 10 years, about 20-35 percent of people with RBD develop Parkinson’s.

“The knowledge that has been gathered about Parkinson’s over the past dozen years has increased tremendously. Canada’s research scientists have contributed so much to furthering our knowledge of the disease, which we now understand is very complex. We know there is not one cause, but many potential culprits.” – Joyce Gordon, President and CEO, Parkinson Society Canada

Although not everyone with RBD will develop Parkinson’s, the strong association between the two suggests that RBD patients should be routinely monitored for Parkinson’s. What’s more, they make an ideal group for studying what might be happening in the early, presymptomatic stages of the disease.

“Our goal is to develop cost-effective screens to identify patients and stop the progression of the disease before symptoms appear,” says Dr. Postuma.

Does Parkinson’s spread like an infection?

Another relatively new idea about Parkinson’s relates to how it spreads in the brain. One theory gaining attention suggests that it may be a prion-like disorder, similar to mad cow disease.

Traditionally, researchers thought that neurons in people with Parkinson’s die because the mechanisms managing natural cell death go awry. In stark contrast, prion diseases are considered infectious: abnormal proteins spread from cell to cell, eventually destroying their host cells.

Recent research suggests that this may be the reason that an abnormal form of a protein called alpha-synuclein accumulates in the brains of Parkinson’s patients. Cellular damage due to this accumulation is “probably one of the most important mechanisms for getting Parkinson’s disease,” says Dr. Fon.

If this is true, it may be possible to develop drugs that stop or slow the spread of this abnormal protein. “If you could put a halt to that, you might be able to get the disease to slow down significantly,” says Dr. Fon. Once again, intervening early — before the disease becomes symptomatic — could be critically important.

“It is an exciting time to work in Parkinson’s disease, says Dr. Fon. “ I think we have a real opportunity to take advantage of some of these leads. Hopefully there will be drugs now that will start to get at some of the underlying mechanisms.”

“Many labs in Canada and elsewhere are working on understanding how defects in these genes and the pathways that they’re involved in could be responsible for Parkinson’s disease.” – Dr. Edward Fon