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Connecting the dots

Hoping to identify better therapies, Michael K. Lee, Ph.D., examines how neurons affected by Parkinson's and Alzheimer's diseases die. (Photo: Scott Streble)

With donors’ support, University researcher pursues the causes of neurodegeneration behind Parkinson’s and Alzheimer’s

Don’t be mistaken: Parkinson’s and Alzheimer’s are distinct neurodegenerative diseases. Both involve the death of neurons, but the primary cells affected are different.

In Parkinson’s disease, most of the killed-off cells are responsible for physical movement. The disease’s most common symptoms, therefore, are motor-related: tremors, stiff muscles, poor balance, and difficulty walking, sitting, or standing.

In Alzheimer’s disease, the destroyed cells are mainly responsible for memory and cognitive skills. Thus, the disease’s key characteristic is gradual cognitive decline, including a devastating loss of memory.

But the two conditions—the most common neurodegenerative illnesses in the United States—do share some hallmark features. Dementia occurs in up to 80 percent of people who have Parkinson’s disease. And many people with Alzheimer’s lose motor function, including their ability to walk, especially toward the end of the illness.

In fact, as scientists learn more about Parkinson’s and Alzheimer’s, they’re discovering that the diseases’ pathological pathways in the brain have much more in common than was previously believed. One of those commonalities is the abnormal behavior of the alpha-synuclein protein.

Through his renowned research on this protein, University of Minnesota neuroscientist Michael K. Lee, Ph.D., is deepening our understanding of how neurons die in both Parkinson’s and Alzheimer’s diseases.

This novel work is pointing to new avenues of therapies that may one day slow or even stop the progression of these two debilitating diseases, which together affect as many as 6 million Americans.

“In both Parkinson’s and Alzheimer’s, the brain just starts dying off,” says Lee, who is codirector of the Center for Neurodegenerative Diseases, part of the Institute for Translational Neuroscience at the University. “We need to stop that if we’re going to have an impact on the progression of the diseases. We have to go beyond just trying to treat the symptoms and get to the underlying processes.”

David and Susan Plimpton understand on a personal level the need to better understand Alzheimer's and Parkinson's diseases. (Photo: Jim Bovin)

A personal interest

Susan and David Plimpton understand on a personal level the urgent need for such research, which is why the couple has made a gift to support Lee’s work. Susan, a former consumer marketing executive, and David, a semi-retired internal medicine physician (and 1966 University of Minnesota Medical School alumnus), also have set aside additional funding for the research in their estate plans.

“I have several family members on my mother’s side who died with severe dementia, and David’s father had Parkinson’s disease with severe dementia,” says Susan Plimpton, who leads a neurosciences development advisory committee for the University of Minnesota Foundation.

Lee’s research “just hit on all cylinders, so to speak, for us,” she adds. “It has the possibility of leading to some important discoveries that might help prevent or manage these diseases more effectively than we do today.”

When a protein turns toxic

Alpha-synuclein is a major constituent of Lewy bodies, the abnormal protein clumps that have long been known as a hallmark of Parkinson’s disease. The protein also becomes abnormal in Alzheimer’s disease. Its precise role in the brain and in the pathology of these diseases is unclear, however.

One of the places alpha-synuclein resides in neurons is an area outside of the nucleus known as the endoplasmic reticulum (ER). The ER functions like an assembly line, synthesizing and “packaging” proteins into folded shapes that enable them to perform specific functions in the cell. If the folding of the proteins is not done correctly, however, the proteins become useless—or, worse, toxic.

Usually, nature takes charge and fixes the problem proteins. Those that are unfolded or misfolded are “caught” and either re-folded or destroyed by proteins called chaperones before they can harm the cell. But as the brain ages, incorrectly folded alpha-synuclein molecules may gather into small toxic clumps called oligomers. Over time, the oligomers may form even bigger clumps, an outcome that can “gum up the entire assembly line of the cell,” says Lee.

The “stressed” ER tries to clean up troublemaking proteins by sending out more chaperones, but if that response is inadequate, explains Lee, “the cell activates a self-destruct mechanism that leads to its death.”

In 2012, Lee and his colleagues were the first to report an association between high levels of alpha-synuclein oligomers and the breakdown of the ER. They found this association both in mouse neurons and in neurons in postmortem human brains.

“We observed it in Parkinson’s disease,” says Lee. “But what we found may also have relevance for Alzheimer’s disease.”

That’s because research suggests that ER stress—the condition triggered by these accumulating toxic clumps—is involved in Alzheimer’s disease as well as in Parkinson’s disease.

Further evidence

To test whether the association he found between ER stress and alpha-synuclein oligomers is an important factor in the death of neurons, Lee teamed up with researchers at Johns Hopkins University to treat mice that model human Parkinson’s disease with salubrinal, an experimental drug that protects cells against chronic ER stress.

“We found that the treated mice were able to survive [without symptoms] for a much longer time,” he says.

In yet another experiment, this time conducted with researchers at the Brain Mind Institute in Lausanne, Switzerland, Lee’s colleagues gave salubrinal to rats that model human Parkinson’s and that have dopamine neurons targeted for death from alpha-synuclein. (Dopamine is a brain chemical critical for coordinating movement, and the loss of dopamine neurons is the major reason for the onset of Parkinson’s.) Once again, the salubrinal dramatically reduced the toxic effects of the alpha-synuclein protein.

Although salubrinal may one day become a good candidate for neurodegenerative therapies, it’s not currently approved for use in humans. Lee and his colleagues are testing other promising drugs, including one already used to treat high blood pressure, in animal models to see whether those compounds also will relieve ER stress.

Lee emphasizes that although the findings from his lab suggest new therapeutic targets, the research is at an early stage. Still, he’s hopeful.

“We need to have a better understanding of the underlying reason the symptoms of Parkinson’s and Alzheimer’s diseases occur,” he says, “so that we can actually help people live longer and have a better quality of life. It’s a big issue—and one that affects not only the individuals who have the disease, but their families as well.”

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