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Mechanism that 'melts' protein clumps may lead to new Parkinson's treatments

Monday October 19, 2015

Catharine Paddock PhD

Medical News Today - A new study provides fresh insights into a possible molecular method for reducing Lewy bodies - protein clumps found in the region of the brain that loses dopamine cells in people with Parkinson's disease.

the human brain
The study proposes two ways that a protein complex may influence the formation of Lewy bodies found in the brains of people with Parkinson's disease.

The research, from Wayne State University School of Medicine in Detroit, MI, is published in The Journal of Biological Chemistry.

There are more than a million people in the US with Parkinson's disease, a devastating and currently incurable brain-wasting disorder that affects movement and coordination. As it progresses, the disease gradually diminishes one's ability to walk, talk and live an independent life.

While nobody has yet discovered the causes of Parkinson's disease, we know that they kill dopamine cells in the brain. Dopamine is a chemical messenger that is essential for sending brain signals that control a number of functions, including movement.

The dopamine-releasing cells most affected by Parkinson's disease are located in a midbrain region known as the substantia nigra pars compacta. A hallmark of Parkinson's disease is the accumulation and progressive spread of protein clumps called Lewy bodies in this region. Lewy bodies contain several proteins, the most common one is called alpha-synuclein.

Because studies show strong links between the presence of Lewy bodies and clinical symptoms of Parkinson's disease, many scientists are coming to the conclusion that they accelerate the disease, which has spurred the search for ways to prevent or get rid of the protein clumps.

The new study, led by Assia Shisheva, a professor of physiology, describes a step forward in the search for a possible way to "melt" the Lewy bodies found in Parkinson's disease.

For some years, Prof. Shisheva's lab has been researching how the behavior of three proteins inside cells are involved with disease. The proteins are two enzymes called PIKfyve and Sac3, and an accessory protein called ArPIKfyve.

The researchers found that these proteins are involved in controlling the traffic of material to the digestive system of the cell. They also found that if the Sac3 enzyme is not bound and protected by ArPIKfyve, it speeds to a hasty death in the cell.

Other discoveries show that mutations in Sac3 are linked to brain degenerating disease in humans, while mutations in PIKfyve are linked to a relatively benign disease in the cornea of the eye.

Two potential ways the protein complex triggers Parkinson's

Putting all these discoveries together led Prof. Shisheva and colleagues to conclude that the double ArPIKfyve-Sac3 complex has separate functions in the brain, and they set out to look for proteins that interact specifically with it.

The new study describes a previously unknown interaction between ArPIKfyve-Sac3 and Synphilin-1, a protein already known to be involved in the development of Parkinson's disease through its interaction with alpha-synuclein, and because like alpha-synuclein, it is also one of the proteins found in Lewy body deposits. Prof. Shisheva notes:

"Our study revealed that the ArPIKfyve-Sac3 complex is an effective inhibitor of aggregate formation by Synphilin-1."

The team also found that if Sac3 levels become excessive, then they trigger protein self-aggregation and clumping by Synphilin-1. This confirms recent research from Japan that found excessive Sac3 accumulates in Lewy bodies, they note.

The researchers therefore conclude there are two ways in which the ArPIKfyve-Sac3 complex may trigger Parkinson's disease. One way is when levels of ArPIKfyve-Sac3 are too low and the other is when levels of Sac3 are too high.

They propose that increasing levels of the ArPIKfyve-Sac3 complex may have a beneficial effect in Parkinson's disease.

Prof. Shisheva suggests that the ArPIKfyve-Sac3 complex works by shifting Synphilin-1 from a clumping form to a more soluble form.

Meanwhile, Medical News Today recently reported how scientists have mapped the path Parkinson's takes as it spreads from affected to healthy brain tissue in the early stages of the disease. In a study published in ELife, the team from McGill University shows how the disease progresses from cell to cell through the brain along networks.

http://www.medicalnewstoday.com/articles/301186.php