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It's A Matter of Debate
If Synucleopathies Look and Act Like Prion Disease, Are They Really Prion Disease?
ARTICLE IN BRIEF
Two movement disorders specialists debate whether Parkinson's disease dementia — with a hallmark of synucleopathies — might be considered a prion disease.
SAN DIEGO—Parkinson's disease dementia — with a hallmark of synucleopathies — might be considered a prion disease, but a debate here among panelists at the International Congress of Parkinson's Disease and Movement Disorders last month appeared to convince most of the audience by a show of hands that it lacked critical criteria for that designation.
The synucleopathies look like prion disease in the brains of Parkinson's disease patients and act like prion diseases, so these synucleopathies are, indeed. prion disease, argued Patrik Brundin, MD, PhD, an associate director of research at the Van Andel Research Institute in Grand Rapids, MI. But another panelist, Glenda Halliday, PhD, a professor of neuroscience at the University of New South Wales in Australia, was unconvinced.
“I agree with everything you said,” she told Dr. Brundin, “and that's why you — the audience — should vote no.” The reason, she asserted: There is no evidence that synucleopathies in Parkinson's disease are infectious – the key criteria for a prion disease.
After a week of lectures that tied synucleopathies to prion-like diseases, co-moderator Anthony Lang, MD, director of neurology at the University of Toronto, suggested that Dr. Halliday had a mountain to climb. But the audience at the start of the 20-minute debate was mixed, and by the end of the session, Dr. Halliday had clearly converted more of the audience to her position.
In laying out his argument that synucleopathies are prions, Dr. Brundin called them pathogens: Prions, or proteinaceous infectious particles, are unconventional infectious agents consisting of misfolded prion protein molecules, he explained, adding that the molecules aggregate with one another and impose their anomalous structure on benign protein molecules.
He demonstrated how the prions recruit other proteins to start the molecular cascade that leads to formation of fibrils. Then, these collections of fibrils evolve into Lewy bodies over long periods of time.
“The important thing to remember is that there is a lag time — an incubation period — from the time of inoculation with the prion until the pathology is widespread,” Dr. Brundin said. He cited studies that showed little transmission for up to 12 years, and then as much as 24 percent of Lewy body pathology appearing at 24 years.
He said that evidence that synucleopathies are prion disease comes from human material, from cell culture experiments, and from animal models. That evidence shows that alpha-synuclein can move from one cell to another; that imported alpha-synuclein can oligomerize with endogenous alpha-synuclein, which constitutes the first step in seeding; and that these imported alpha-synuclein fibrils can generate Lewy body aggregates.
Dr. Brundin said that the in vitro and in vivo science has been backed by findings in multiple clinical settings, where Lewy body pathology has been observed in Parkinson's disease patients. “This is the real deal,” he said.
Other experiments show that in cell cultures, synuclein can develop into clusters that look like Lewy bodies, he said. “When you inoculate animals, you can get progressive — the key word — synucleopathy and it follows distinct pathways. You can do this with brain extracts that contain misfolded synuclein; you can make synthetic fibrils or you can actually take human autopsy material and inject it into animals...These experiments can trigger Parkinson's disease in mice and even in monkeys.” He said the culprit lesions “look like Lewy bodies.”
Dr. Brundin argued that “the time has come to modify the definition to encompass the full scope of the prion paradigm in biology and to accommodate the many instances in which proteopathic diseases lack an infectious origin. This expanded and refined definition could help to obviate unnecessary confusion and concern about the communicability of noninfectious proteopathies and speed acceptance of this important paradigm within the biomedical community.”
Dr. Halliday, however, was unconvinced. “If we take the infectious concept out of the argument, then everything that Patrik said would be fine,” she said in urging the audience to support her thesis, “but it is the infectious concept that makes prions special.
“As a neuroscientist, if I have a prion disease that comes across my desk, it is reportable, like every other infectious disease that is communicable to herds, like us,” Dr. Halliday said. But, she said, there is no evidence that synucleopathies are communicable. As an example, she cited studies that showed no transmission through surgical specimens in recipients of cadavaric human growth hormone.
She said that alpha-synuclein and prions have similar biochemical characteristics: both have oligomer and fibril formation; both have high content beta-sheet; both exhibit insolubility in mild detergents; both show partial resistance to proteinase K; and both have conformation diversity.
When it comes to transmission, Dr. Halliday noted that both prions and alpha-synuclein can spread from cell to cell, and both can spread in an organism. But there is no spread among individuals with alpha-synuclein and there is no spread of strains with alpha-synuclein — both characteristics of prions.
The question, she said, is whether synucleopathies can be transmitted from one person to another, from one species to another without assistance, or spread though the food chain.
In addition to the problems with transmissibility, Dr. Halliday said that in the laboratory, alpha-synuclein looks different than prions. One of those differences, she said, is that prions appear to cause large, spongy holes due to vacuoles in neurons, while alpha-synuclein shows no neuronal changes other than their appearance in Lewy bodies. Another difference is the appearance of astrogliosis without inflammation with prion disease and an inflammatory reaction without astrogliosis in alpha-synuclein disorders. “There is really something very different about what is happening to the protein,” Dr. Halliday said.
She said that studies have not shown any evidence of transmission of alpha-synuclein disease among patients who need frequent blood transfusions, and she said there was no evidence of the key lag time for development of the disease in populations that should be at risk.
Dr. Halliday also noted that the incidence of Parkinson's disease has remained static while Alzheimer's disease has increased, indicating a lack of growth in synucleopathies. “So there doesn't seem to be any evidence of transmission, which, for me, is comforting,” she said.
She said her colleagues and her research were unable to find evidence of synucleopathies' transmission from non-human pathways, “so it looks like we can't get it through the food chain.” On the other hand, prion disease appears transmissible from species to species.
“I have no doubt that alpha-synuclein is a self-propagating pathogenic protein, but I don't think it is a prion,” Dr. Halliday concluded.
After calling for another vote by hands, moderator Dr. Lang noted that Dr. Halliday had succeeded in overcoming the prevailing sentiments and had carried the debate.