The quest for the holy grail in parkinson’s disease

Michael Schlossmacher

Michael Schlossmacher and his team investigate the relationship between a gene, a protein and approved drugs in the hope of finding a cure for Parkinson’s.

To design a new drug, test it through clinical trials and get it on the market costs millions of dollars and can take a decade or more. But if Michael Schlossmacher and his team are right, a drug that is already approved might save time, money and, most importantly, bring relief to people with Parkinson’s disease.

Schlossmacher, a University of Ottawa neurologist who holds the Canada Research Chair in Parkinson’s Disease and Translational Neuroscience, was recently awarded the Bhargava Research Chair in Neurodegene ration at the Ottawa Hospital Research Institute. He is studying the link between a gene called GBA1, a protein called alpha-synuclein and rapamycin, a drug that helps prevent rejection of transplanted organs.

Researchers have already demonstrated that most people with typical Parkinson’s disease have greater levels of alpha-synuclein accumulated in their brain cells than people without Parkinson’s. The protein clumps together in neurons, killing brain cells that produce dopamine, a chemical that enables neurons to communicate with each other. Loss of this chemical messenger contributes to the motor symptoms, such as stiffness, slowness and tremors, that Parkinson’s patients typically experience.

People with two mutated copies of GBA1 in each cell develop Gaucher disease, a rare genetic disorder that causes problems in the liver, spleen, bone marrow and sometimes in the nervous system. People with Gaucher disease or with one mutated copy of GBA1 are at a higher risk for Parkinson’s.

Recent genetic studies suggest that more than 10 percent of all people with typical Parkinson’s may carry one mutated copy of GBA1, identifying it as the most common genetic risk factor and a potential treatment target for Parkinson’s.

Schlossmacher discovered in 2011 that the normal form of GBA1 may play a protective role in the disorder. Working with Genzyme Corporation of Cambridge, Mass., Schlossmacher and his colleagues established that extra amounts of the enzyme the GBA1 gene produces can reduce the amount of alpha-synuclein in the brain cells of mice with Parkinson’s-like behavioural changes. In these mice, extra amounts of GBA1 injected into the brain not only clear clumps of alpha-synuclein in affected brain cells, they also improve the rodents’ performance on memory tests.

Academia-based laboratories, pharmaceutical companies, private foundations and federal funding bodies in the United States are exploring whether the GBA1-alpha synuclein link could be used to stem the process of neurodegeneration in people with Parkinson’s disease. Genzyme sells an intravenous drug for enzyme replacement therapy to treat Gaucher disease. Now Schlossmacher wants to find out whether other drugs could also halt the process that causes alpha-synuclein to clump and kill brain cells.

Schlossmacher’s team wants to test whether feeding rapamycin and other approved drugs to mice with Parkinson’s-like symptoms also lowers the amount of alpha-synuclein in brain cells, just as introducing more GBA1 did. “If we were successful with exploiting this connection between GBA1 and alpha-synuclein with already approved drugs,” he says, “we could potentially make a difference (in Parkinson’s disease).”

In the meantime, there is no cure for Parkinson’s—only treatment to control symptoms. “It’s not good enough anymore to improve a little bit of memory function or a little bit of tremor through therapy,” he says. “What we need to do is to get to the root cause of Parkinson’s. That’s how we will arrest this disease.”

Schlossmacher believes the relationship between GBA1 and alpha-synuclein is taking scientists closer to the fundamental cause of the disease and its ultimate treatment—the holy grail in Parkinson’s research.


by Laura Eggertson

David Park

David Park has genetically engineered a mouse model to help researchers solve the puzzle of this progressive brain disorder.

One of the biggest stumbling blocks to studying Parkin son’s disease has been the lack of an animal model researchers can use to test theories on how the neurodegenerative disorder starts, how it progresses and whether it can be stopped, reversed or treated. David Park, a University of Ottawa professor of cellular and molecular medicine, has recently created a mouse model that will propel investigations forward into how and why dopamine-producing brain cells die, causing Parkinson’s.

“Now we can study the process—that’s why it’s so significant,” says Park, who is also assistant dean of research in the Faculty of Medicine.

Previously, the only mouse models available were exposed to toxins to produce Parkin son’slike symptoms. But researchers now know that only a small percentage of people afflicted with Parkinson’s were actually subjected to toxins. Those models did not reflect the source of Parkinson’s in the vast majority of people living with the disease.

Park and his team have genetically engineered mice so that they are missing a gene, DJ-1, which is linked to the familial, or inherited, form of Parkinson’s disease. They then bred a line of mice with the same genetic background. Those mice have motor symptoms similar to Parkinson’s and, just as in humans, they begin to show more symptoms as they age.

Researchers need to be more confident that the results they produce and the medication or other therapies they try will actually reflect what happens in humans, says Park. Since researchers cannot, of course, readily experiment on humans, they need these mouse models, he adds.

“Having an appropriate surrogate is critical in narrowing down what you think is going to be important,” he says. That is especially true in testing potential targets for new or existing drugs to not only relieve symptoms, but one day cure or prevent Parkinson’s.

Park uses this mouse model to investigate the brain signals that tell neurons they are damaged and should die. The death of neurons that generate dopamine, a signalling chemical in the brain, causes the motor symptoms such as stiffness and tremors that typically affect Parkinson’s patients. If researchers could interrupt that signalling process, they might prevent the death of those cells.

The lack of an appropriate model is one of the reasons previous clinical trials to test potential treatments for Parkinson’s may have failed, Park notes.

Now “you can test particular drugs or gene therapy interventions on the mouse models at particular stages in the (degenerative) process and figure out when they will be most effective,” says Park. Having the mouse model will accelerate research into Parkinson’s, saving years of trial-and-error approaches.

Pinpointing the process that results in Parkinson’s disease is like assembling a complex jigsaw puzzle. “From an intellectual level, it’s an incredibly difficult and convoluted puzzle that needs solving,” he says. “From a patient level, you see people who suffer from Parkinson’s disease and you want to help in every way you can. It’s a whole range of reasons that coalesce into making me passionate about what I do.”

The mice, Park believes, will finally help researchers put the jigsaw puzzle together.


by Laura Eggertson

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