PIND researchers find why alpha-synuclein is key in Parkinson’s disease

Courtesy J. T. Greenamyre

Researchers headed by Love Family professor of neurology J. Timothy Greenamyre, MD, PhD, have uncovered a major reason why the Parkinson’s-related protein alpha-synuclein is toxic to neurons in the brain. Alpha-synuclein is a major constituent of the Lewy bodies that are the pathological hallmark of Parkinson’s disease.The finding has the potential to lead to new therapies that could slow or stop progression of the devastating illness. The new research appears in Science Translational Medicine.

Hear Greenamyre discuss his group's findings on NPR's WESA.

Parkinson's is a degenerative neurological disease characterized by tremor, slowness, and gait and balance difficulties that affects about 1 million people in the United States. The symptoms are caused by the degeneration and loss of neurons in the brain, particularly those crucial for the initiation and coordination of movement.

“It’s really exciting that we have found a mechanism we can target to create new treatments for this devastating disease,” said Greenamyre, who directs the Pittsburgh Institute for Neurodegenerative Diseases (PIND).

PIND’s goal is an integrated, interdisciplinary approach to the study of neurodegenerative diseases and their mechanisms, with the aim of transforming cutting-edge science into novel therapies and diagnostics that directly benefit individuals affected by neurodegenerative diseases.

“With four different PIND investigators working together, the new study highlights the power of this collaborative approach,” Greenamyre added.

Current treatments for Parkinson's can reduce symptoms, but they do not slow the inevitable worsening of the disease. To slow or halt illness progression, scientists must first determine why and how the neurons are dying.

Degenerating neurons contain large clumps of a protein called alpha-synuclein. People whose cells make too much alpha-synuclein or make a mutated form of the protein are at high risk of developing Parkinson's because of the protein’s toxicity, researchers found. Scientists also demonstrated that the accumulation of alpha-synuclein in Parkinson's is toxic because it disrupts the normal functioning of mitochondria—the tiny powerhouses responsible for generating a cell’s energy.

In the new study, Greenamyre and his team—led by coauthors Roberto Di Maio, PhD, and Paul Barrett, PhD, both of PIND—used a well-established rodent model of Parkinson's to show exactly how alpha-synuclein disrupts mitochondrial function. They found that by attaching to a mitochondrial protein called TOM20, alpha-synuclein prevented the mitochondria from functioning optimally, which resulted in the production of less energy and more damaging cellular waste.

Ultimately, this interaction between alpha-synuclein and TOM20 leads to neurodegeneration, Greenamyre explained.

The researchers then confirmed their animal findings in brain tissue from people with Parkinson's disease. (Image: In dopamine neurons from individuals with Parkinson’s disease, depicted in blue, there is abnormal interaction of alpha-synuclein with the mitochondrial receptor TOM20. The alpha-synuclein-TOM20 interaction is depicted in red.)

“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,” said Greenamyre.

Using cell cultures, the research team also found two ways to prevent the toxicity caused by alpha-synuclein: Gene therapy that forced the neurons to make more TOM20 protein protected them from the alpha-synuclein; and a protein that was able to prevent alpha-synuclein from sticking to TOM20 prevented alpha-synuclein’s harmful effects on mitochondria.

While more research is needed to determine whether these approaches could help Parkinson's patients, Greenamyre is optimistic that one or both may ultimately make it into human clinical trials in an effort to slow or halt the otherwise inevitable progression of the disease.

Coauthors of the study are Charleen Chu, MD, PhD, Edward Burton, MD, PhD, Teresa Hastings, PhD, Eric Hoffman, PhD, Caitlyn Barrett, PhD, Alevtina Zharikov, PhD, Anupom Borah, PhD, Xiaoping Hu, and Jennifer McCoy, all of PIND.

This work was supported by research grants from the DSF Charitable Foundation, the Ri.MED Foundation, the Consolidated Anti-Aging Foundation, the National Institutes of Health, the United States Department of Veterans' Affairs, the Blechman Foundation, the American Parkinson Disease Association and the Department of Biotechnology, Government of India.

--Allison Hydzik