Parkinson’s disease, a neurodegenerative disease that results from the death of dopamine-releasing neurons in the brain, affects more than 10 million people worldwide, according to the Parkinson’s Foundation. Although the disease includes a variety of symptoms, patients often experience shaking or tremors, slowness of movement, or trouble balancing.
For the past two summers, senior Taylor Zimmer worked as a research intern at Van Andel Research Institute, working with a specific protein related to Parkinson’s disease to help develop a diagnostic test and model of the disease.
Although approximately 60,000 new cases are found each year in the U.S. alone, according to the Parkinson’s Foundation, there is no definitive diagnostic tool for Parkinson’s disease, and the exact mechanism behind cell death remains unknown.
“Currently, if you were to go to the doctor, there are no tests they can give you to diagnose the disease” said Katelyn Becker, a senior research technician in the lab where Zimmer worked. “They will look at your symptoms and take a good guess, and they’re right about 70 – 80 percent of the time. This is because the symptoms are overlapping between different neurodegenerative diseases, and unfortunately by the time the symptoms are noticeable, the damage to the neurons is already done.”
Although the symptoms are similar between different neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, the progression and cause of the diseases in the brain are very different. This can make drug trials difficult, Becker said.
“A drug might help with Parkinson’s disease, but when you have patients with other diseases in the study, you wouldn’t be able to see the effect, so that limits our analysis of what’s working,” Becker said.
In turn, distinguishing effective drugs for Parkinson’s disease could help researchers determine the mechanism by which the disease causes neuron death in the brain.
Zimmer’s work focused on a single protein, alpha synuclein, a protein that is thought to be involved in vesicle transport at the juncture between two neurons. The misfolded alpha-synuclein protein, however, forms fibrils that clump together and are thought to cause cell death.
Zimmer spent one summer working with variations of the alpha-synuclein protein to see if one of them could be used as a part of a diagnostic tool for Parkinson’s disease. Alpha-synuclein fibrils are able to seed the growth of more alpha synuclein fibrils from native monomer alpha synuclein.
Examining the effects of various mutations on this seeding ability could prove useful to determining whether alpha synuclein fibrils can be used as a biomarker of Parkinson’s disease.
“For example, if a biological sample from a PD patient contained small amounts of alpha synuclein fibrils, you could take that sample and test the seeding ability,” Zimmer said. “If it did seed, that would say that they had PD. If it didn’t grow at all or had a long lag time for growing fibers, then they don’t have PD.”
Zimmer said of the variants she tested, she was able to identify one variant that showed promise for use as
a diagnostic tool. She also helped improve a protocol for quickly weeding out variants that were not candidates for use in this test.
“That’s kind of a never-ending project because there are thousands and thousands of variants,” Zimmer said. “At the very end of the summer, I got one out of the eight that I tested that seemed like a really good candidate.”
This past summer, Zimmer continued her work with the alpha-synuclein protein, this time developing a way
to fluorescently label the protein so it could be studied and observed in cells. She said it was the first time that this labeled alpha-synuclein protein was made into fibrils using ultrasound, and she had to determine whether this method of tagging the protein would interfere with its ability to form fibrils. She then examined the seeding capability of the tagged protein when added to cells.
“First, I had to go through the process and see how well the labeled alpha synuclein grows into fibrils in vitro,” Zimmer said. “You have to characterize its growth before you can test it in other models.”
Becker said the Ma laboratory, which focuses on prion mechanisms in neurodegenerative diseases, will continue working to create a model of the disease and potential diagnostic tools.
“We’re trying to work at it from all angles — there isn’t a good Parkinson’s disease model yet, so that’s really limiting when you’re trying to figure out the cause of a disease,” Becker said. “Unfortunately that just one of the huge challenges with the research we’re doing right now.”