One protein could help stop the aggregation of another protein called alpha-synuclein (aSyn) that tends to build-up in the brain cells of many patients with Parkinson’s disease.
HYPE, the only Fic protein found in humans, is a key regulator of whether cells live or die under stress. In order to work properly, proteins need to fold in the correct shape. When cells are stressed, their proteins can become misfolded, at which point they can aggregate and become toxic. Cells sense stress by assessing the amount of misfolded proteins within them.
“Since HYPE plays such an important role in how cells deal with stress from misfolded proteins, we wondered whether diseases that result from protein misfolding were likely to need HYPE,” says Seema Mattoo, an assistant professor of biological sciences at Purdue University. “We know that in Parkinson’s disease, often the misfolded protein is aSyn. So we asked if HYPE could modify aSyn, and if so, what are the consequences?”
The study shows that HYPE does modify aSyn—and that this new modification, called AMPylation, decreases aggregation.
FIGHTING LEWY BODIES
Clumps of aSyn, known as Lewy bodies, are the pathological hallmark of Parkinson’s disease. Aggregated aSyn can poke holes in the membranes of neurons, which causes a decline in nerve function and messes up how nerve cells communicate.
To figure out if lower aggregation of aSyn actually translates to fewer poked holes, Mattoo worked with Jean-Christophe Rochet, a professor of medicinal chemistry and molecular pharmacology, to mimic a membrane using different lipids and then compare how the modified and unmodified aSyn fared against it. The lipids were loaded with dye, which would leak out if holes were poked.
“We found that less dye was released with the modified aSyn, meaning the membrane stayed more intact,” says Mattoo, who is also a member of Institute of Inflammation, Immunology, and Infectious Disease and Center for Cancer Research. “That means HYPE could possibly have a therapeutic effect on Parkinson’s disease.”
Prior to this study, AMPylation of aSyn, which reduces aggregation, had never been seen before. Many modifications of the protein occur naturally, but they tend to increase aggregation.
When Mattoo’s team looked at modified aSyn under an electron microscope, they also found that the structure of the protein had changed. Normal aSyn tends to twist, which could promote aggregation. But the new, modified version doesn’t twist as much—it forms parallel fibers, which might be why it aggregates less, Mattoo says.
THE DIFFICULTY OF TREATING PARKINSON’S DISEASE
About 60,000 Americans are diagnosed with Parkinson’s disease each year, affecting roughly 1 percent of the population over the age of 60. It manifests in shakiness, stiffness, and difficulty with walking, balance, and coordination, as well as mental and behavioral changes. There is no cure for the disease, but medication can help reduce symptoms.
Parkinson’s disease is difficult to treat because its true cause is poorly understood, and no one understands the real function of aSyn. Researchers know its aggregation promotes the disease, but why does the cell allow it to aggregate in the first place? Why is aSyn there to begin with? While aSyn’s exact biological function remains unknown, researchers are hesitant to attack the protein because it is important for the survival of nerve cells.
“We’re all trying to apply a Band-Aid at the end of disease progression because we know aggregation causes the cells to become toxic, but how can we prevent that?” Mattoo says. “There is still much to be understood mechanistically about it in the context of disease.”
The study was done in vitro, but the next step is to move it into brain cells, and then into an animal model.
“We’re in the early stages, but these results are giving us a new angle to look at potential therapeutics,” Mattoo says. “We’re trying to come up with drugs that could be used to manipulate HYPE’s activity. You could give them to patients who are starting to show signs of Parkinson’s or who are prone to having aggregated aSyn. That’s the direction we want to go.”
The research appears in the Journal of Molecular Biology.
Funding for the research came from the National Institutes of Health; Indiana Clinical and Translational Sciences Institute; Purdue Institute for Inflammation, Immunology, and Infectious Disease; the Branfman Family Foundation; Purdue Research Foundation; Purdue’s Cancer Prevention Internship Program; and Eli-Lilly-Stark Neuroscience Research Institute.
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