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2017 Annual Report

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Beyond the Brain Do the

Beyond the Brain Do the secrets of Parkinson's lie in the nose, the gut and inflammation? In 1817, British surgeon James Parkinson penned the first medical description of the disease that now bears his name. He chronicled a singular, inexplicable disorder that afflicted his patients — usually people advanced in age — with tremors and rigidity, eventually robbing them of their ability to move. Two hundred years have passed since then, and in many ways, the causes of Parkinson’s have continued to defy definition. But now, thanks to recent breakthroughs and technological advancements, scientists are chipping away at the seemingly impenetrable façade of Parkinson's disease, revealing a complex tapestry of causes, symptoms and molecular mechanisms that may revolutionize patient care and improve the lives of millions around the globe. Connecting the dots For much of the time since the initial publication of James Parkinson’s Essay on the Shaking Palsy, Parkinson’s disease was considered a purely motor condition, largely attributed to a brain progressively starved of the neurotransmitter dopamine, which controls voluntary movement. Like many other conditions, Parkinson's was viewed as one disease with likely one cure out there somewhere, waiting to be discovered. The reality, said Dr. Patrik Brundin, Van Andel Research Institute associate director of research, isn’t quite so clear cut. “Parkinson’s is an incredibly diverse disease and can vary widely from person to person,” Brundin said. “Its study and treatment necessitate a sophisticated approach and require us to recognize there may not just be one solution but many.” Under Brundin’s leadership, scientists in the Institute’s Center for Neurodegenerative Science working with collaborators around the world are tackling Parkinson’s from every angle, investigating its risk factors, its causes and its vulnerabilities. Their goal? To find ways to slow or stop its progression, something no current therapy can do. Moving past motor symptoms We now know that a host of seemingly unrelated symptoms can predate a Parkinson’s diagnosis by years, or even decades. Chief among them are the loss of a person’s sense of smell and intestinal issues, such as constipation. “For a long time, we didn’t entirely grasp the significance of these other, non-motor symptoms,” Brundin said. “Now, we understand they are not only important precursors but also hint at the very basis of the disease itself. If we understand what’s happening early on in the disease, before motor symptoms appear, we can harness that knowledge to find ways to slow or possibly prevent it.” In a series of discoveries, the most recent published in 2017, Brundin’s team revealed how a toxic protein called alpha-synuclein, long linked to Parkinson’s, travels from the nose into the olfactory bulb, the area of the brain responsible for processing scents. From there, these proteins move from cell to cell, clogging up the molecular machinery required to keep cells healthy and functioning. These proteins eventually reach a region rich with dopamine-producing cells, where scientists theorize alphasynuclein wreaks havoc, killing cells and starving the brain of the chemical needed for movement. The nose isn’t the only place harboring a reserve of toxic proteins with a direct route to the brain. Something similar may also be happening in the gut, which is connected to the brain via the “superhighway” of the vagus nerve, one of the longest nerves in the human body. It’s here that Assistant Professor Dr. Viviane Labrie is searching for reasons why normal alpha-synuclein changes into its toxic form and how this process — and its spread to the brain — could be prevented. “While the gut and the nose are clearly very different, they have one important thing in common — frequent contact with the outside world, through breathing and food consumption, respectively,” Labrie said. “Although environmental factors play a role in Parkinson’s disease, they can’t be the only things. We all breathe, and we all eat, but we all don’t get Parkinson’s. There has to be something else at play.” The tipping point The secret may lie, at least partially, in yet another normal process gone haywire. Inflammation is the body’s response to insult or injury, a manifestation of a marshaled immune system that sends a chemical flood to help heal a wound or respond to a stressor. There is a catch though — for inflammation to help rather than hurt, it must be silenced when it’s no longer needed. When inflammation sticks around, it can disrupt normal cellular function, interfering with processes such as the removal of toxic forms of alphasynuclein. “We’re learning, thanks to intense research in our lab and in the labs of our colleagues, that inflammation likely plays a central role in the incredibly complicated process that triggers Parkinson’s,” said Associate Professor Dr. Lena Brundin. “Reducing inflammation is a promising therapeutic strategy that may provide a tremendous opportunity to 6 | VAN ANDEL INSTITUTE ANNUAL REPORT 2017

RESEARCH attack the disease from a new direction.” Here again, the nose may harbor important clues. Fueled by a set of new Department of Defense grants totaling .37 million, Dr. Patrik Brundin and collaborators at University of Southern California and Michigan State University are investigating the role of air pollution as a potential contributing factor to Parkinson’s. Their theory? That environmental factors such as pollution build on a person’s specific genetic influences and age — the single greatest risk factor for Parkinson’s — setting off an uncontrolled inflammatory chain reaction. Bringing it together In all, Parkinson’s is likely the result of a complex mix of genetics, epigenetics and environmental triggers that set a cascade of problems into motion. Some cause the abnormal clumping of alpha-synuclein, turning it from a harmless protein into a toxic one, while others bog down cellular machinery, interfering with processes designed to keep cells healthy. Genetic and epigenetic factors almost certainly are at play as well, influencing individuals’ risk of developing the disease. Each newly identified contributing factor reveals a chink in the armor of Parkinson’s, ripe for targeting by new or repurposed medications. “We’ve come a long way since James Parkinson put ink to paper, from viewing the disease as a one-size-fits-all motor disorder to our current understanding of Parkinson’s as a diverse multi-system event,” Dr. Patrik Brundin said. “Together with collaborators around the world, our scientists are pushing forward quickly. We’re on the edge of ushering in a monumental change in how Parkinson’s patients are diagnosed and treated. I’m more excited — and hopeful — now than ever before.” (LEFT TO RIGHT) DR. VIVIANE LABRIE, DR. LENA BRUNDIN & DR. PATRIK BRUNDIN. VAN ANDEL INSTITUTE ANNUAL REPORT 2017 | 7

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