Finding the Key to Parkinson’s Disease Neurodegeneration

Issue Date: 
July 11, 2016

Researchers at the University of Pittsburgh School of Medicine have uncovered a major reason why a brain protein linked to Parkinson’s disease is toxic to neurons in the brain.

The finding has the potential to lead to new therapies that could slow or stop progression of Parkinson’s, a devastating illness that affects about one million people in the United States. The new research appeared in the June 8, 2016, issue of Science Translational Medicine.

Parkinson’s is a degenerative neurological disease characterized by tremors, slowness, and gait and balance difficulties. The symptoms are caused by the degeneration and loss of neurons in the brain, particularly those crucial for the initiation and coordination of movement.

J. Timothy Greenamyre“It’s really exciting that we have found a mechanism we can target to create new treatments for this devastating disease,” said lead investigator J. Timothy Greenamyre, professor and chief of the new Movement Disorders Division, Department of Neurology, Pitt’s School of Medicine, and director of the Pittsburgh Institute for Neurodegenerative Diseases (PIND).

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

Degenerating neurons contain large clumps of a brain 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 and Paul Barrett, both of PIND—used a well-established rodent model of Parkinson’s disease 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. Di Maio is a research associate, and Barrett is a postdoctoral fellow, both in Greenamyre’s lab.

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.

“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.

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