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Is Parkinson Disease a Prion-Like Disease? Experts Say Yes (Maybe)


doi: 10.1097/01.NT.0000368122.21665.11
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A theory gaining traction among some Parkinson disease (PD) experts is that PD may be a prion-like disorder, based on evidence that alpha-synuclein can be transmitted from neuron to neuron, leading to the development of Lewy body-like inclusions in the receiving cell, and other findings from neuroanatomy, fetal transplantation surgery, and basic science.

Is Parkinson disease (PD) a prion-like disorder, with alpha-synuclein playing the role of infectious protein? The answer to that provocative question may be “yes,” according to a growing number of PD experts, as they consider findings from neuroanatomy, fetal transplantation surgery, and basic science.

“I don't think the case is air-tight yet, but it's an exciting hypothesis,” said C. Warren Olanow, MD, professor of neurology at Mount Sinai School of Medicine in New York City. “It's a new way of looking at PD, which, if correct, would suggest novel therapies.”

Dr. Olanow posed the prion question, along with Stanley Prusiner, MD, in a commentary accompanying a research study in the August 2009 issue of the Proceedings of the National Academy of Sciences.

That study — led by Paula Desplats, PhD, and colleagues at the University of California-San Diego — showed that alpha-synuclein can be transmitted from neuron to neuron, leading to the development of Lewy body-like inclusions in the receiving cell.

Dr. Desplats co-cultured mouse neuronal stem cells with neurons that over-expressed human alpha-synuclein. Within 24 hours, half the stem cells had picked up alpha-synuclein via endocytosis, leading to the development of protein aggregates. Stem cells transplanted into synuclein-expressing mice also developed aggregates, although not as quickly or as extensively.

“We'd been thinking that alpha-synuclein aggregation was just an internal affair of the cell, but now we see it may be due to other external factors,” Dr. Desplats said.

That result, remarkable by itself, might nonetheless have been dismissed as a benchtop curiosity, but for two other recent findings from postmortem evidence.



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The first arose from a tour-de-force of neuropathology by Hieko Braak, MD, and colleagues at Goethe University in Frankfurt, Germany. They conducted hundreds of postmortem examinations of patients with PD and unaffected individuals, staining the brain for alpha-synuclein, the core protein of Lewy bodies.

Unaffected individuals were not free of Lewy bodies, but they only occurred in structures below the substantia nigra, specifically the olfactory structures and the dorsal motor nucleus of the vagal nerve. In most PD patients, they were found in all the lower structures, plus the nigra, and, in more advanced cases, the cortex.

From the consistency of this pattern, Dr. Braak proposed that PD involved a spread of Lewy pathology from the lower structures to higher ones. The classic motor symptoms only develop, and the disease would only be diagnosed when it reached the substantia nigra. But, he said in a lecture in 2005, “it can be argued that so-called incidental Lewy bodies are pathological entities, even when present in minimal numbers, and these inclusion bodies represent the presymptomatic correlates of PD.”

The proposal fit well with the growing appreciation of the early, non-motor symptoms of PD, and the long-recognized risk for dementia in advanced PD. Most PD experts embraced Dr. Braak's concept of preclinical progression, even though no mechanism for the spread was apparent.

The second finding arose from postmortem examination of three patients who had received fetal dopamine neuron transplants a decade or more before. A minority of grafted neurons had developed Lewy bodies, the first time alpha-synuclein pathology had been observed in such young neurons, and suggested that the PD disease process had spread from sick neurons to healthy ones.

This was the context that made the Desplats discovery so intriguing to PD researchers, including Dr. Olanow. As in classic prion diseases, “the critical features are misfolding, aggregation, and spreading,” he said.

Like cellular prion protein, alpha-synuclein can adopt two conformations — an alpha helix and a beta sheet — and like prion protein, the misfolded beta conformation leads to aggregation, with small misfolded clusters “seeding” the misfolding and aggregation of yet more protein. Dr. Desplats showed that this propensity to aggregate can spread from one neuron to another.

In this “prion model” of PD, some still-unknown environmental trigger causes protein misfolding in neurons linked to the outside world, such as those in the olfactory structures or the gut. “Those are two potential entry points,” Dr. Olanow said.

The early involvement of the gut might explain the history of constipation so common in patients, while olfactory compromise would explain the common history of hyposmia, both of which precede clinical PD by years.

Eventually, an overload of misfolded protein would lead to aggregation within the neuron, and its release and uptake by adjacent neurons, spreading the disease upward through the CNS. The severity of the aggregation or timing of its release might be influenced by the known genetic risk factors for PD, at least some of which have roles in protein handling.

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“Independent of oxidative stress, mitochondrial dysfunction, iron accumulation, and all the other hypotheses of PD pathogenesis, this hypothesis suggests that part of, if not a major component of, the process is triggered by neuron-to-neuron transmission of misfolded protein. It is clearly a very interesting speculation,” said Anthony Lang, MD, professor of neurology at the University of Toronto. The spreading pattern observed by Braak “would fit nicely with neuron-to-neuron transfer,” he added.

Nonetheless, “the evidence remains to be developed and established,” Dr. Lang said. In the known prion diseases, the rate of progression after symptom onset is much more rapid than PD. “We have to postulate a very slow spread indeed,” he added, in contrast to the rapid release and uptake seen in the experiments by Dr. Desplats.

Current animal models of PD may not be adequate to fully establish the prion hypothesis, since they do not develop Lewy bodies. “We need more representative animal models,” he said.



“I think the idea is very powerful,” said William Langston, MD, director of the Parkinson's Institute in Sunnyvale, CA. Taken together, the evidence is pointing toward alpha-synuclein trafficking as critical to disease progression. “If I had to guess, the next epoch in neuroprotection is going to be about trafficking,” to try to halt the disease. There is a developing consensus that the reason attempts at neuroprotection haven't been more successful is that we are getting in so late'.

The emerging model suggests the time to intervene would be years before diagnosis, while the disease is still confined to lower brain structures. If the prion model is confirmed, it would lend urgency to development of wide-scale screening tools, such as smell testing, to identify those at risk.

“It's such a tantalizing time in Parkinson disease research,” Dr. Langston said. “You can see it kind of coming together.”

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Olanow CW, Prusiner SB. Is Parkinson's disease a prion disorder? Proc Natl Acad Sci USA 2009;106(31):12571–12572. E-pub 2009 Jul 28.
    Desplats P, Lee HJ, Lee SJ, et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci USA 2009;106(31):13010–13015. E-pub 2009 Jul 27.
      ©2010 American Academy of Neurology