Researchers have revealed a major reason why proteins that are the hallmark of Parkinson’s disease are toxic to neurons in the brain. The discovery could be key to finding a way to slow or halt the disease.

Lead investigator J. Timothy Greenamyre, a neurology professor at the University of Pittsburgh School of Medicine, said:

“It’s really exciting that we have found a mechanism we can target to create new treatments for this devastating disease.”

It was known that the accumulation of a protein called α-Synuclein and dysfunction of mitochondria are key to the degeneration seen in most forms of Parkinson’s disease, and that the two factors appear to be related, but just how has remained unclear.

Alpha-synuclein Toxicity

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, Greenamyre and colleagues found.

They also demonstrated that the accumulation of alpha-synuclein is toxic because it disrupts the normal functioning of mitochondria, the tiny powerhouses responsible for generating a cell’s energy.

This results in the production of less energy and more damaging cellular waste, ultimately leading to neurodegeneration.

The researchers confirmed their findings in brain tissue from people with Parkinson’s.

Gene Therapy

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 of a mitochondrial protein called TOM20 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.

“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,” says Greenamyre.

Although further research is needed to determine whether these approaches could help people with Parkinson’s, Greenamyre is optimistic that one or both may ultimately make it into human clinical trials.

The research was supported by the DSF Charitable Foundation, the Ri.MED Foundation, the Consolidated Anti-Aging Foundation, the National Institutes of Health, the US Department of Veterans’ Affairs, the Blechman Foundation, the American Parkinson Disease Association, and the Government of India’s Department of Biotechnology.

Roberto Di Maio, et al α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease Science Translational Medicine; Vol. 8, Issue 342, pp. 342ra78 DOI: 10.1126/scitranslmed.aaf3634

Image: Abdiel Ibarra

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