A research team led by Virginia Lee, who works as a neurobiologist at the University of Pennsylvania in Philadelphia has provided a mechanism for how misfolded proteins cause Parkinson’s disease. Lee’s group has resurrected an old treatment strategy that was discarded long ago that just might to slow the progression of this neurological disease.
Alpha-synuclein is a strange name for a protein, but it is a specifically found in the nervous system. Alpha-synuclein protein can compose as much as 1% of all the protein in the cytoplasm of a neuron. It is found all over the brain. What this protein actually does is a bit of a mystery, but the latest data suggests that alpha-synuclein helps traffic proteins from membranes to other places in the cell (Cooper et al., (2006). Science 313: 324–328).
In the brains of patients with Parkinson’s disease, neurons accumulate protein aggregates known as Lewy bodies. A major component of Lewy bodies is alpha-synuclein that has folded in an aberrant manner. These aggregations of misfolded alpha-synuclein cause a variety of problems inside cells that culminate in the death of the neuron.
This is the story of Parkinson’s disease so far, but Lee and her colleagues injected a misfolded synthetic version of α-synuclein into the brains of normal mice and saw the key characteristics of Parkinson’s disease develop and progressively worsen. While that is not a surprise, what Lee and co-workers found when they examined the brains of the injected laboratory animals astounded them. This study, which was published in the journal Science, shows that the injected misfolded alpha-synuclein was able to spread from one nerve cell to another. Therefore, the malformed protein did not just take up residence inside neurons, but instead was able to travel from one neuron to another.
Apparently, cells affected by misfolded alpha-synuclein are able to secrete it into the areas that surround them and this secreted protein is taken up by healthy cells. Once taken up, the misfolded alpha-synuclein induces the normal copies of the alpha-synuclein protein snap into the misfolded conformation. This eventually kills off the once-healthy neuron and also turns it into a new factory for the secretion of misfolded alpha-synuclein, which them goes on to damage other neurons.
This finding, however, raises the possibility that an antibody that binds the misfolded α-synuclein could potentially bind the protein and prevent it from passing between nerve cells. “It’s 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 tendency of the pathology of Parkinson’s disease to spread from neuron to neuron by a rogue protein was actually suggested in 2008. Fetal neural tissue transplants were used to treat Parkinson’s patients, but upon post-mortem examination of the transplanted fetal tissue, it was quickly recognized that these transplants has developed the characteristic Lewy bodies associated with Parkinson’s disease. This indicated that the nearby diseased cells were able to infect the transplanted tissue with Parkinson’s disease. Subsequent studies have shown that misfolded alpha-synuclein does spread between neighboring cells and induce cell death (Desplats, P. et al. Proc. Natl Acad. Sci. USA 106, 13010–13015 (2009).). The neurons, apparently, can release vesicles filled with misfolded alpha-synuclein in the same way they release neurotransmitters. This release bathes the nearby cells in misfolded alpha-synuclein, but there are still questions as to whether or not the misfolded alpha-synuclein is responsible for the cascade of brain damage seen in Parkinson’s.
Lee says that her team has now captured the full consequences of runaway α-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.
Besides Lewy bodies, the brains of patients with Parkinson’s disease also show a dramatic loss of those neurons that produce the chemical messenger dopamine. When Lee’s team injected the misfolded α-synuclein into a part of the mouse brain rich in dopamine-producing cells, Lewy bodies began to form, followed by the death of dopamine neurons. Nerve cells linked to those near the injection site also developed Lewy bodies, which showed that cell-to-cell transmission was occurring.
Greenamyre says that is possible, but hasn’t yet been proved. “All of the cells affected in this paper were those directly in contact with the injection site,” he says. But, within six months of the injection, coordination of movement, grip strength and balance had all deteriorated in the mice, which is a recapitulation of what occurs in people with Parkinson’s disease.
“It’s really pretty extraordinary,” says Eliezer Masliah, a neuroscientist at the University of California, San Diego. “We have been trying that experiment for a long time in the lab and we have not seen such dramatic effects.” According to Masliah, Lee’s work provides the impetus for that handful of biotechnology companies that are sponsoring clinical trials of alpha-synuclein antibodies for as therapeutic agents for Parkinson’s disease. Masliah hopes that this will also motivate neuroscientists to examine exactly how the protein enters and exits cells.
There is still one mystery that has not been addressed to data: why do the Lewy bodies appear in the first place? “Parkinson’s disease is not a disorder in which somebody injects synuclein into your brain,” notes Ted Dawson, director of the Institute for Cell Engineering at Johns Hopkins University in Baltimore, Maryland. “So what sets it in motion?” Clearly some mutations in the gene that encodes alpha-synuclein increase the tendency for this protein to spontaneously misfold. But this also suggests that there are particular triggers that lead to such events. The nature of these triggers will certainly be the subject of future work.