Researchers suggest new theory for how Parkinson's disease develops

Associate Professor Simone Engelender of the Technion-Israel Institute of Technology and her colleague Ole Isacson at Harvard Medical School describe this "threshold theory" of Parkinson's for the first time in a report published in the January issue of Trends in Neuroscience.

"Instead of studying how proteins move from one neuron to another and searching for compounds that prevent the 'spread' of aggregated α-synuclein, we need to study why α-synuclein accumulates within neurons and how these neurons die in the disease, and search for compounds that prevent the general neuronal dysfunction," said Professor Engelender.

Parkinson's disease destroys nerve cells throughout the body, especially key neurons in the brain that produce a compound called dopamine that helps to control movement and posture. The disease grows worse over time, and there is no known cure. More than one million people in the United States have the disorder, according to the Parkinson's Disease Foundation.

The disease is caused by accumulation of α-synuclein, which overwhelms and destroys nerve cells. The most commonly-held theory about the disease suggests that patients get progressively worse as clumps of α-synuclein spread between neurons, almost like an infection.

But Engelender and Isacson think the scientific evidence points to a different model of the disease. Instead of spreading from neuron to neuron, they say, aggregations of α-synuclein develop throughout the body at the same time. Different parts of the nervous system vary in how much of this toxic protein they can tolerate, depending on how well the cells in that part of the system work together to compensate for any destroyed cells.

The researchers say their theory fits better with patients' symptoms than the infection-style theory. Engelender and Isacson's theory may help explain, for example, why some of the earliest signs of the disease appear in places like the gastrointestinal tract that have no neurons to compensate for a dysfunction and therefore have a lower threshold of tolerance for α-synuclein toxicity.

The new theory may also affect how the disease is treated. For instance, some scientists have recommended a procedure that severs part of the vagus nerve, which runs outside the brain, to prevent the spread of α-synuclein from the body to the brain. The threshold theory, Engelender said, suggests that this operation would be unnecessary.

"The only specific treatment that is and will continue to be beneficial is the replenishment of dopamine in the brain, through the intake of the supplement L-Dopa, to improve the motor symptoms," said Engelender. "This has been done for several decades and should be continued to be done since it can at least alleviate the motor symptoms for a few years, even if does not cure and does not prevent the progression of the disease."

"Nevertheless, I believe that the search for compounds that specifically decrease α-synuclein levels are the only hope to provide a real and more effective treatment for the disease," Engelender added.