Damaged Protein Reveals Parkinson’s Destructive Course

Damaged Protein Reveals Parkinson’s Destructive Course in Mice
Digital illustration comparing dopamine levels in a normal neuron and one affected by Parkinson's disease. The Parkinson's affected neuron on the left produces a very low level of the neurotransmitter dopamine. The neuron on the right supplies a normal amount of dopamine to the synapse. Photographer: Carol and Mike Werner/Photo Researchers

A rogue protein injected into the brains of mice led to a cascade of effects that culminated in Parkinson’s-like symptoms in an experiment that may, for the first time, establish the disease’s path of destruction.

Healthy mice injected with the abnormal protein began producing it in their brains, leading to clumps of the substance called Lewy bodies. The clumps in turn caused loss of dopamine-producing neurons that are key to motor control, according to a study in the journal Science.

Loss of the nerve cells causes difficulty in moving, a trait of Parkinson’s disease. Both Lewy bodies and loss of dopamine-producing neurons had been linked to the illness. Until now, it wasn’t clear how the two were linked together, said study author Virginia M.-Y Lee, the director of the Center for Neurodegenerative Disease Research at the University of Pennsylvania.

“You have a bad protein in a bad shape, and it can corrupt normal protein into a bad shape and spread itself,” Lee said in a telephone interview. “It really resolves a controversy. Obviously when you have two types of pathology, you want to link them, to see if there’s a relationship.”

What’s more, the experiment may provide a better model for Parkinson’s research. Current models either produce Lewy bodies or kill off the dopamine-producing neurons, Lee said. With this advance, scientists can now create mice with both, allowing for better testing for potential Parkinson’s remedies.

Misfolded Protein

The lab created a misfolded, or damaged protein, instead of using a brain tissue sample, for purity. If they’d used a brain tissue sample, it might have been inadvertently contaminated with something else, Lee said. The protein, called alpha synuclein, is a hallmark of Parkinson’s and some other brain ailments. By using the pernicious protein alone, Lee’s group established it’s solely responsible for the Parkinson’s-like symptoms.

About a month after the bad protein was injected into the mice’s brains, the researchers saw more of them rippling through the brain. After three months, a sixth of the brain cells that generate dopamine were gone, and the mice did worse on tests of their coordination and balance than non-injected peers.

Parkinson’s has no cure; the gold standard for treating the disease is levodopa or L-dopa, which boosts dopamine levels in the brain. The drug becomes less effective after years of use.

An experimental treatment where healthy dopamine-generating neurons were grafted into the brains of Parkinson’s patients showed that the healthy transplants were corrupted by Lewy body structures over time. Today’s experiment may help explain why.

Much more work remains, Lee said. She hopes as many other labs as possible will replicate her experiment. Her group will work on an antibody therapy that aims to stop the spread of the misfolding protein.

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