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VAI Voice

The Official Blog of Van Andel Institute
7 Nov 2017

Stemming inflammation offers new hope for treating Parkinson’s disease

For the seven to 10 million people worldwide with Parkinson’s disease, a medication that actually slows down their disease and staves off its debilitating symptoms would be a game-changer.

Developing such a treatment has proven difficult over the years, mostly because of the complex factors underlying the disease, many of which still aren’t completely understood. But now, thanks to a slate of new findings from scientists around the world, that could change.

“Increasing evidence suggests that chronic inflammation may be at the root of many disorders, including Parkinson’s,” said Dr. Lena Brundin, a physician-scientist at Van Andel Research Institute. “Inflammation is a critical defense mechanism that amps up our biological response to injuries and infection but, when it continues past the point it is supposed to stop, it can be incredibly damaging.”

In a comprehensive research review published last week in Journal of Parkinson’s Disease, Brundin and her colleagues Dr. Patrik Brundin and Dr. Viviane Labrie theorize that a faulty enzyme tightly linked to inflammation may propel the spread of Parkinson’s through the brain by disrupting the critical systems required to keep cells healthy and functioning. Called ACMSD, this enzyme offers a promising target for new medications designed to halt Parkinson’s progression and give people more years with fewer symptoms.

“The brain is in a constant chemical balancing act,” said Labrie. “When the scale tips too much in one direction, its effects can snowball, much to our detriment. That’s what we’re seeing with ACMSD, inflammation and Parkinson’s.”

In healthy cells, ACMSD limits the production of a neurotoxin called quinolinic acid, which is generated during inflammation brought on by a host of factors such as genetic mutations, environmental influences, infections and even the makeup of the bacteria in the gut. If ACMSD isn’t present and functioning correctly, quinolinic acid levels can spike, triggering a vicious circle of inflammation and neurotoxicity that can be catastrophic, ultimately damaging and killing brain cells.

Dr. Lena Brundin’s previous research linked reduced activity of ACMSD to depression and increased risk for suicide while others have found hints that it may be associated with several other neurological disorders. The possible link to Parkinson’s, however, is relatively recent; over the past few years, multiple large genetic studies have connected the enzyme with a heightened risk for developing Parkinson’s.

“Our theory ties together many important threads across the spectrum of Parkinson’s research. Now, we urgently need to understand how ACMSD interacts with other molecular events linked to Parkinson’s,” says Dr. Patrik Brundin. “To our knowledge, there is no therapeutic development underway that targets ACMSD. Our review is proof of concept that perhaps there should be.”

Current treatment options for Parkinson’s are limited; levodopa, the gold standard drug therapy, and deep-brain stimulation, a surgical option, help manage symptoms, but do not correct the underlying problem. Both become less effective over time and come with their own sets of challenging side-effects.

To remedy this, scientists have been on the hunt for new drug targets that can be modified to restore normal function, thereby treating the disease. Several promising leads have been identified but, until relatively recently, ACMSD was not among them, Dr. Lena Brundin says.

Going forward, the team plans to further investigate the link between ACMSD, inflammation and Parkinson’s, including early lab results that indicate a loss of ACMSD causes the brain cells affected by the disease to progressively die.

“We hope that this theory represents a watershed moment in Parkinson’s research,” Dr. Lena Brundin says. “More work is required to fully explore the role ACMSD may play in Parkinson’s and how it might be leveraged therapeutically. Regardless of the findings, they will tell us something we didn’t know before and help us get one step closer to better treatments.”

This work was supported by the KiMe Fund and the Michael J. Fox Foundation for Parkinson’s Research.

TERMS TO KNOW

Parkinson’s disease: Once thought to be purely movement-related, Parkinson’s disease has emerged in recent years as a multiple system disorder, with non-motor symptoms such as depression and loss of sense of smell affecting people years before the onset of hallmark symptoms like tremors and slowness of movement. It is a progressive neurological condition that currently has no cure and no way to slow its progression.

Inflammation: Inflammation is the body’s response to an injury, infection or other insults. During this process, inflammatory chemicals are released to help the body either heal and fight off invading pathogens. However, when the mechanisms that keep inflammatory responses in check go awry, these chemicals can be overproduced and have harmful side-effects.

ACMSD: ACMSD is an enzyme, a type of protein that facilitates important reactions and processes throughout the body. It keeps inflammatory chemicals, such as quinolinic acid, in check.

Quinolinic acid: Quinolinic acid is an inflammatory, excitatory neurotoxin that is regulated by ACMSD. It is a by-product of a complex cascade of chemical reactions required for normal brain function.

Enzyme: Enzymes are molecules that accelerate the chemical reactions that are critical for healthy function.