Puzzling Out Parkinson’s Progression

Researcher seeks understanding of disease’s origins

A decade ago, Rush University Medical Center researcher Jeffrey Kordower, PhD, was part of a group of scientists that made an electrifying discovery about Parkinson’s disease.

They were the first to see that some fetal cell grafts that had been injected into a patient’s brain during a clinical trial several years previously — cells that were thought to be resistant to Parkinson’s disease – were displaying a signature marker known as “Lewy bodies,” clusters of a toxic variation of the protein alpha-synuclein. The pathogen had traveled from diseased cells in the patient to the new, ostensibly healthy ones.

The discovery turned the field of Parkinson’s disease research on its head, but it was only the beginning. Today, Kordower, The Alla V. and Solomon Jesmer Professor of Neurological Sciences at Rush, and an international authority on movement disorders, is investigating a whole bevy of startling hypotheses he and his colleagues have built from similarly dogged and ingenious investigations. They include the notions that Parkinson’s disease actually may originate in the gut, and that the cause of disease progression may be the spreading of misfolded proteins that in turn cause normal proteins of misfold as well. (Misfolded proteins are abnormal proteins that clump together.)

Kordower counts among the proudest achievements of his career that “we have made inroads into understanding the pathogenesis (development) of Parkinson’s.”

Internationally recognized for ‘high-quality work’

For two decades, Kordower and the lab he oversees at Rush have been at the forefront of new discoveries about Parkinson’s disease. Known as PD for short, it’s the second-most common neurodegenerative disease, with more than a million suffering from it in the United States alone.

Kordower is the director of the Rush Research Center for Brain Repair, has more than 400 papers and book chapters to his credit, and holds or has held numerous leadership positions at medical journals and organizations. His research on neurodegenerative disease, including Alzheimer’s and Huntington’s diseases, has appeared in such prestigious journals as Nature, Science and the New England Journal of Medicine, and he is one of the most-cited researchers in the field — which reflects both the importance of his work, and his colleagues’ faith in it.

“We think our lab is internationally recognized because we do high-quality work,” he says.

Preventions and treatments for Parkinson’s are urgently needed

There presently is no cure for PD, which is chronic and progressive — that is, it gets worse over time. It occurs most commonly in the elderly, and results from the death of a large number of neurons, or brain cells, in a particular part of the brain called the substantia nigra. The disease’s distinctive marker is the presence of Lewy bodies in that area, and a big part of Kordower’s research is trying to understand better how and why they develop.

Symptoms of the disease include a slowing of movement, diminishment of the ability to plan movement, abnormal stiffness, and uncontrollable movements (tremors) in resting limbs. Early symptoms can include disordered sleep and changes in the way odors are perceived. Later in the course of the disease, PD patients can also fall or develop dementia, two leading causes of nursing-home admissions. Finding a cure or a way to prevent the disease, as well as treatments that ease its symptoms, are urgent goals.

A drug called Levodopa can be an effective treatment for PD, but while it provides relief, it doesn’t stop the ravages of the disease. Also, Levodopa usefulness tends to diminish over time due to the emergence of serious side effects.

“We need new therapies and strategies” for PD, Kordower says.

Studies include groundbreaking gene therapy research

One possibility is a type of gene therapy that uses stem cells, unspecialized fetal or “reprogrammed” adult cells. Such cells can release dopamine, a neurotransmitter that facilitates movement, into the brains of individuals with PD to subdue the symptoms of the disease. Kordower was the first researcher to demonstrate, in a paper published in 1995 in the New England Journal of Medicine, that such grafts, with fetal “dopaminergic” (dopamine-releasing) cells, can “do all the things we want them to do.” Those desired tasks include survive, form synapses in the brain, and restore nerve function and motor control to patients with Parkinson’s disease.

In a study published in Science in 2000, Kordower’s team showed that ferrying certain “trophic factors” — different types of molecules that help neurons communicate — into the brain in a genetically modified virus kept PD symptoms at bay. It was in this type of injected stem cells that Kordower and his colleagues later saw Lewy bodies. “However we need to find biomarkers that will identify who will get PD so these trophic factors can be more effective’ Kordower says.

Could Parkinson’s originate in the gut?

One of the great mysteries of PD has been the origin of Lewy bodies, and a theory now holds that the disease might get its start in a patient’s digestive system. Kordower, his Rush colleague Ali Keshavarzian, MD, a gastroenterologist, and colleagues have demonstrated that people diagnosed with PD dependably have alpha-synuclein – the protein related to Lewy bodies – and evidence of inflammation in their colons. (A-synuclein is most commonly, though not exclusively, found in the brain.)

In fact, researchers are exploring whether this type of colon inflammation when a-synuclein colonies are present might be a marker of PD, even before the symptoms of motor impairment appear. The inflammation itself could be causing a-synuclein to “mis-fold.”

“PD may be a disease, that spreads from elsewhere in the body to the brain and then throughout the brain,” Kordower says. This theory “has changed the way people think about therapeutics. It’s the most exciting hypothesis.”

In this hypothesis, PD is akin to diseases caused by prions, proteins that can fold themselves abnormally in ways that can be transmitted to other prions, triggering a chain reaction that causes disease. Prions cause Creutzfeldt-Jacob, a fatal, infectious brain disease in humans, and “mad cow disease” in livestock.

Abnormally folded protein is present in PD as well, but Kordower thinks PD is caused not by an actual prion, since PD is not transmitted between people as prions can be. Rather he thinks it may be caused by a particle that has some things in common with prions. Kordower thinks the particle may cause protein in neurons (cells) in the brain to mis-fold, and to spread the mistake to other neurons.

Finding his way

A psychologist by training, Kordower says he got into neuroscience as an undergraduate who had “not much direction” at Queens College in New York. He worked with Richard Bodnar, PhD, a psychologist-neuroanatomist who studied the mechanisms of pain perception and analgesia (the inability to feel pain).

Kordower’s own father suffered from a chronic disease, Crohn’s disease, and Bodnar’s research on pain seemed not only interesting but also important. Kordower joined Bodnar’s lab, and says now it was one of the best decisions he ever made.

“He’s the best,” Kordower says of Bodnar. “He changed my life.”

Kordower’s dissertation, at the City University of New York, was on analgesia reversed by vasopressin, a hormone involved in maintaining water balance in the organism. He completed a post-doctoral fellowship at the University of Rochester in New York, then came to the University of Illinois at Chicago. While there, Kordower participated in a collaboration with Rush researchers on Alzheimer’s disease that resulted in an invitation to come work at the Medical Center. He made the move in 1990.

From bench to bedside

While Kordower conducts his research in laboratories, his translational science studies have led to seven clinical trials so far. He says that most basic researchers feel lucky to have one such experience. None of these trials has resulted in a treatment — indeed, they have all sent Kordower back to the lab to try out different hypotheses, or at least variations on them.

That process is the normal course of scientific inquiry, Kordower notes; it takes time and many trials to develop a hypothesis that proves entirely correct. Still, being able to watch his basic science translate to clinical trials is something he especially values about the collaborative environment at Rush.

“Other hospitals talk about taking research from bench to bedside, but at Rush, it really happens,” Kordower says.