Misfolded protein transmits Parkinson ’s from cell to cell

Protein clumps called Lewy bodies (centre) found in Parkinsons disease are caused as misfolded -synuclein moves from cell to cell.

Kelvin Luk/Univ. Pennsylvania/Science AAAS

The catastrophic damage wreaked by a rogue protein involved in Parkinsons' disease has been tracked by researchers, in work that might help to reinvigorate an old treatment strategy to slow the condition.

A team led by Virginia Lee, a neurobiologist at the University of Pennsylvania in Philadelphia, injected a misfolded synthetic version of the protein -synuclein into the brains of normal mice and saw the key characteristics of Parkinsons disease develop and progressively worsen. The study, published today in Science1, suggests that the disease is spread from one nerve cell to another by the malformed protein, rather than arising spontaneously in the cells.

The finding raises the possibility that an antibody that binds the misfolded -synuclein could be used to intercept the protein as it passes between nerve cells. Its very hard to ask antibodies not only to get inside the brain, but to get inside cells, says Lee. But now you have the possibility of stopping the spreading. And if you stop the spreading, perhaps you can slow the progression of the disease.

The idea that Parkinsons might be spread from neuron to neuron by a rogue protein took off in 2008, when transplants of fetal nerve tissue given to patients with the disease developed the characteristic clumps associated with the condition2, 3. This indicated that the nearby diseased cells had somehow infected the transplanted tissue. Subsequent studies showed that misfolded -synuclein can spread between neighbouring cells4 and can cause cell death5.

But the question remained as to whether the misfolded -synuclein was responsible for the cascade of damage seen in Parkinsons. Lee says that her team has now captured the full consequences of runaway -synuclein in the brain.

We knew this transfer from one cell to another can happen, but whether it could play a significant role in the disease was still open, says Tim Greenamyre, director of the Pittsburgh Institute for Neurodegenerative Diseases in Pennsylvania, who was not involved in the latest work.

Parkinsons disease has two distinct features: clumps of protein called Lewy bodies and a dramatic loss of nerve cells that produce the chemical messenger dopamine. When Lees team injected the misfolded -synuclein into a part of the mouse brain rich in dopamine-producing cells, Lewy bodies began to form. This was followed by the death of dopamine neurons. Nerve cells that linked to those near the injection site also developed Lewy bodies, a sign that cell-to-cell transmission was taking place, say the researchers.

Greenamyre says that that is possible, but hasnt yet been proved. All of the cells affected in this paper were those directly in contact with the injection site, he says.

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Misfolded protein transmits Parkinson ’s from cell to cell