Researchers Confirm that Clumps of Alpha-synuclein, the Pathological Hallmark of PD, Can Spread from Cell to Cell Within the Brain
This past month, a team of researchers from the University of Pennsylvania published a paper confirming that clumps of the protein alpha-synuclein, the pathological hallmark of Parkinson's disease, can spread from cell to cell within the brain. This supports a new emerging scientific understanding of alpha-synuclein, and could open up new approaches to develop treatments that target the protein.
Initial reports compared the spreading of these clumps, called fibrils, to prions -- infectious proteins capable of transmitting disease from one organism to another. Prion diseases include bovine spongiform encephalopathy (BSE) ("mad cow") disease, most commonly transmitted to humans when they eat food contaminated by the brain, spinal cord or digestive tract tissue of infected cattle. Alpha-synuclein is not infectious, however, and there is absolutely no evidence that PD can spread from person to person.
The Michael J. Fox Foundation (MJFF) spoke about the study with Patrik Brundin, MD, PhD, professor of neuroscience at Lund University in Sweden, who recently completed an MJFF-funded study similar to that of the University of Pennsylvania team, and Mark Frasier, PhD, director of research programs at MJFF.
MJFF: Dr. Frasier, how significant are the study's findings?
MF: This study is quite significant because it may furnish a better understanding of the biology of alpha-synuclein. Alpha-synuclein is a protein in the brain that is of great interest to Parkinson's researchers because it is a major constituent of Lewy bodies, protein clumps that are the pathological hallmark of PD. We used to believe that these clumps stayed within the cell. For this reason, the scientific community was largely focused on developing therapies to be delivered into the cell. The new findings present the hypothesis that while alpha-synuclein is made within the cell, it may then be secreted and taken up by other cells, spreading throughout the brain. This may drive new approaches to alpha-synuclein targeted treatments for PD.
MJFF: Dr. Brundin, how do your own study's results complement the University of Pennsylvania study?
PB: The University of Pennsylvania study adds a lot of support to the idea that PD may have a prion-like component to it. Prions are proteins that can spread from cell to cell or human to human or animal to human, and cause disease.
Our project finished in June, and was very much in line with the Pennsylvania group's findings. We are working in vivo (within a whole living organism); their study was in vitro (whereby a component of an organism like a cell is isolated from the organism itself). In our MJFF-funded work, we also studied the prion-like transmission of alpha-synuclein, and demonstrated that alpha-synuclein can move from cell to cell in pre-clinical model of PD.
MJFF: Does this mean that brain diseases like Parkinson's are "contagious"?
PB: No. There is no evidence whatsoever that PD can be transmitted from person to person. Our findings indicate that alpha-synuclein spreads inside the brain, but not between individuals. In effect, it is the disease process that spreads, in the shape of the misfolded alpha-synuclein protein, from one brain region to another.
MJFF: Tell us more about the history of the study of prion-like phenomenon in PD.
PB: Data supporting the idea of a prion-like phenomenon in Parkinson's is very recent. In 2005, John Hardy, PhD, chief of the Laboratory of Neuroscience at the National Institute on Aging, published a short review article that suggested that a prion-like mechanism could contribute to PD and other related diseases, but the experimental evidence took a few more years to arrive.
In 2008, both our team and Jeff Kordower, PhD, the director of the Research Center for Brain Repair at Rush University Medical Center in Chicago, showed what we believed to be transmission of human alpha-synuclein to grafted cells in PD patients, opening what we believed to be new experimental approaches toward understanding the causes of PD onset and progression.
Through post-mortem analysis of the brains of PD patients who had undergone transplantation surgery to graft healthy fetal tissue into their brains during the late 1980s and early 1990s, we found that some neurons in the grafts had developed PD-like pathology over the course of 11 to 16 years. The primary change observed in the grafted fetal tissue was the emergence of Lewy bodies. This observation provided us with a hint to what is going on in the underlying disease-causing mechanism of PD; namely, that it progresses slowly and is capable of spreading from an affected brain region to a new, healthy site.
Following these results, the field started to take off. When we published our work back in 2008 in Nature Medicine, a reviewer labeled our hypothesis an "unsubstantiated fantasy." Now, three years later, we feel there is some real substance behind this idea. And thanks to the Pennsylvania paper, we have further strong biological evidence that this prion phenomenon maybe does occur in PD. It's been quite a fast progression.
Now we are trying to understand how we could inhibit the progression of the disease, and therefore, about how we might develop a drug that stops this spreading from one cell to another. In other diseases that are closely related to Parkinson's like ALS and Alzheimer's, there are studies showing a similar phenomenon with proteins called superoxide dismutase and tau, respectively. These studies, I believe, are changing the whole research landscape. If we can understand the mechanism whereby the disease-related proteins move between cells, it could open up avenues for developing novel therapies, not only PD, but for other neurodegenerative diseases as well.
MJFF: What are your team's next steps?
PB: We are now moving forward with funding from the European Research Council. We will be able to spend the next few years working on developing different pre-clinical models to explore what the mechanisms are of alpha-synuclein seeding, and then interfere in these models pharmacologically. The hope is that we will find a drug that at least partially inhibits this transfer of alpha-synuclein without disrupting normal brain function. If we could do this we could delay the development of PD.
MJFF: Dr. Frasier, does the recent study impact any other work being funded by the Foundation?
MF: This study could, in fact, strengthen the rationale for an approach from Austrian biotech AFFiRiS for a first-of-its-kind vaccine approach for PD. We are currently funding AFFiRiS to conduct a Phase 1 clinical study of its vaccine candidate AFFITOPEŽ PD01, which stimulates the body's immune system to produce antibodies that bind to alpha-synuclein, clearing it from the brain and slowing disease progression. While we are optimistic about the potential of the AFFiRiS vaccine, it is important to stress that this approach is still in the early stages of clinical testing.
There is still a lot to be learned about how alpha-synuclein spreads in the brain. Just this past week at the PD Therapeutics Conference in New York, Pennsylvania's Dr. John Trojanowski presented further findings from in vivo pre-clinical experiments that demonstrated similar results to the group's previous study - namely, that alpha-synuclein can spread within the brain.