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Answers about alpha-synuclein
PITTSBURGH—Some of the latest research out of the University of Pittsburgh School of Medicine—for which the American Parkinson Disease Association (APDA) was a funding partner—has revealed one of the major reasons why alpha-synuclein, a significant component of the Lewy bodies that characterize Parkinson’s disease, proves toxic to neurons.
The findings appeared in Science Translational Medicine in a paper titled “α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease.” The study’s lead investigator was Dr. J. Timothy Greenamyre, Love Family Professor of Neurology in Pitt’s School of Medicine and director of the Pittsburgh Institute for Neurodegenerative Diseases (PIND), who also serves as the director of the APDA Advanced Center for Parkinson’s Disease Research at PIND and a member of the APDA Scientific Advisory Board.
“It’s really exciting that we have found a mechanism we can target to create new treatments for this devastating disease,” Greenamyre remarked in a press release. “I’ve been involved in Parkinson’s research for more than 25 years, and the further I go along, the more urgency I feel to translate what we’re doing in the laboratory into something that’s going to make a meaningful difference for people affected by Parkinson’s disease. I believe these findings will have a lot of impact in the Parkinson’s research community. We couldn’t have done it without the support of APDA.”
In Parkinson’s disease, the failing neurons contain large clumps of the protein alpha-synuclein. Individuals whose cells produce too much of the protein, or a mutated form, have a high risk of developing Parkinson’s disease due to alpha-synuclein’s toxicity.
Alpha-synuclein is a naturally produced protein, but much like amyloid beta—one of the main culprits of Alzheimer’s disease that, it was recently discovered, is generated by the brain as an antibiotic—is not harmful in its normal form and in normal amounts. As Greenamyre tells DDNews, “We do not really understand [alpha-synuclein’s] normal function; however, if we make too much of it—by virtue of our genetic makeup or in response to environmental toxins—it can change its structural characteristics in ways that make it toxic. By the same token, if we have genetic mutations and make abnormal forms of the protein, it may be toxic.” Though cells can generally clear excess alpha-synuclein through various mechanisms, he adds, “defects in the clearance mechanisms may predispose to PD.”
It has also been established that the protein’s toxicity is due to the fact that the excess alpha-synuclein disrupts the normal functioning of mitochondria.
This latest work uncovered how that functioning is disrupted. In a rodent model, Greenamyre and his team, lead by Drs. Roberto Di Maio and Paul Barrett, both coauthors from PIND, found that alpha-synuclein attaches to a mitochondrial protein known as TOM20, which prevents mitochondria from functioning properly, which in turn results in the production of less energy and more cellular waste.
TOM20, as Greenamyre explains, “plays a key role in recognizing proteins destined for going into mitochondria. If TOM20 cannot function normally, mitochondria cannot import—and ultimately do not contain—the proteins they require for normal function.”
“The effects of alpha-synuclein on mitochondria are like making a perfectly good coal-fueled power plant extremely inefficient, so it not only fails to make enough electricity, but also creates too much toxic pollution,” he said.
These findings were also confirmed in brain tissue from individuals with Parkinson's disease.
Armed with this knowledge, and using cell cultures, the team was able to find two ways to prevent the toxicity that alpha-synuclein causes: a gene therapy that made neurons produce more TOM20 protected them from alpha-synuclein, and a protein that was capable of preventing alpha-synuclein from sticking to TOM20 prevented the former's impact on mitochondria.
Greenamyre says the team is looking forward to identifying which species of alpha-synuclein are toxic and the common mechanisms for causing toxicity, as well as new avenues for therapeutic intervention. Their next step will be to evaluate their newly discovered therapeutic strategies in a rat model of Parkinson's disease, in hopes that it will translate into clinical trials in humans, he adds.