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Prion-Like Pathology Seen in Animal Model of Multiple System Atrophy

Samson, Kurt

doi: 10.1097/01.NT.0000441299.44544.2d
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Investigators reported that human multiple system atrophy can be transmitted into mice injected with homogenates from patients with confirmed disease, and that the animals develop alpha-synuclein brain aggregates in a pattern suggesting a prion-like etiology.

A team of prion researchers at the University of California, San Francisco (UCSF) have found that human multiple system atrophy (MSA) can be transmitted into mice injected with homogenates from patients with confirmed disease, and that the animals develop alpha-synuclein brain aggregates in a pattern suggesting a prion-like etiology.

The findings, reported Nov. 11 in an early release by the Proceedings of the National Academy of Sciences, add to a growing body of evidence that supports the hypothesis that misfolded alpha-synuclein protein in MSA, like Parkinson disease (PD) and Lewy body dementia, has prion-like properties.

The research was conducted by researchers working in the laboratory of Stanley B. Prusiner, MD, director of the Institute for Neurodegenerative Diseases at UCSF, who won the 1997 Nobel Prize in Medicine for discovering prions.

MSA is caused by the accumulation of misfolded alpha-synuclein protein in cells that produce dopamine as well as oligodendroglia, which form the myelin sheath that surrounds axons in the central nervous system. These self-propagating proteins with abnormal structures spread from cell to cell, and there is growing evidence that they may play a role in other alpha-synucleinopathies, including PD and Lewy body dementia, because these diseases involve multifocal central nervous system degeneration, dementia, and cerebellar ataxia.

“Our results provide compelling evidence that alpha-synuclein aggregates formed in the brains of MSA patients are transmissible, and what we observed fits the profile of a prion disorder,” said lead author Joel Watts, PhD, who was a postdoctoral fellow in Dr. Prusiner's laboratory during the study and is currently an assistant adjunct professor at the University of Toronto's Center for Research in Neurodegenerative Diseases.

“Not everyone is convinced about prions in these diseases, but our study showed that human homogenates of MSA caused alpha-synuclein aggregates after these misfolded proteins entered new cells and began spreading. This is an important finding,” he told Neurology Today in a telephone interview.

“The MSA prion represents a unique human pathogen that is lethal upon transmission in mice and is reminiscent of the prion that causes kuru, he noted, but our findings are not as disturbing as they might seem. Human-to-human transmission might be possible through contaminated surgical instruments, but it would be very difficult unless these misfolded proteins were somehow introduced directly to the brain.”

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The UCSF researchers tested the transmission theory in mice that had a matched pair of chromosomal alleles for the transgene — that is, they were homozygous for the mutant A53T alpha-synuclein transgene — and could develop degenerative systems, and those that were “normal” and lacked the dual effect, and wouldn't be expected to develop symptoms. Homozygous mice spontaneously develop progressive neurological disease system symptoms at around 10 months while their hemizygous counterparts do not.

They injected the hemizygous mice with the human MSA homogenate preparation — tissue processed into a fluid — and found they developed progressive neurodegenerative symptoms at around 100 days. To demonstrate transmission from mouse to mouse, they inoculated the hemizygous mice with aggregates from homozygous mice with the mutated 53T alpha-synuclein transgene; and found they developed neurologic problems at around 210 days.

The brains of the mice injected with human MSA aggregates showed prominent astrocytic gliosis, microglial activation, and widespread deposits of phosphorylated alpha-synuclein that were proteinase K sensitive, detergent insoluble, and formic acid extractable, all signs of prion-like disease.

“Although some investigators prefer to use alternate terms to describe the recently recognized prion proteins involved in PD, Alzheimer's disease, and the tauopathies, the shared features of these protein-mediated degenerative diseases are increasingly becoming more apparent,” said Dr. Watts.

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Commenting on the findings, Patrik Brundin, MD, PhD, the Jay Andel endowed chair in Parkinson Research and director of the Center for Neurodegenerative Science at the Van Andel Institute in Grand Rapids, MI, agreed that if MSA is a prion disease, human transmission has yet to be demonstrated and, even if it is, the risk is very small.

“I find the findings intriguing, but for human transmission huge amounts [of mutated alpha-synuclein from patients with MSA] would have to be injected directly into the nervous system,” he told Neurology Today in a telephone interview.

He noted that migration of alpha-synuclein and consequent neurological deterioration was reported six to seven years ago, but as yet research has not been able to explain it.

“Some researchers advocate that these should be called prions, and we know alpha-synuclein plays a role in Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer disease, but I think the National Institute for Neurological Disorders and Stroke wants to avoid categorizing such proteins as prions, so the term ‘prion-like’ is used — I like that. For the public the word prion can be frightening, so ‘prion-like’ seems to work.”

In 2008, Dr. Brundin was part of a team that discovered that PD patients who received fetal dopaminergic neuron grafts and survived for years, eventually developed alpha-synuclein-positive Lewy bodies in the grafted neurons.

“It was tremendously exciting for us at the time and the field has moved a lot in just a few years, but this is just the beginning. It will be difficult to really understand what is going on until imaging for alpha-synuclein is developed.”

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Maria Herva Moyano, PhD, a senior research associate in the department of clinical neuroscience at the Cambridge University Center for Brain Repair in London, is currently developing a transgenic mouse line to help better understand if and how misfolded alpha-synuclein can spread from the gastrointestinal system to the brain. She has also created a fast and reliable method to form alpha-synuclein aggregates with the aim of using it as a high content assay to screen for drugs with anti-aggregating properties.

“Overall, the data in this article add further evidence to the idea that many human neurodegenerative diseases, such as Parkinson's disease, MSA, and even Alzheimer's are prion diseases,” she told Neurology Today. “Using prion expertise to study these other diseases will definitely help us better understand how the diseases develop and progress, as well as what might be done to stop that progression.”

She noted that using human homogenates of the protein, as the authors did, resulted in faster transmission despite having a lower content in oligomers, which they suggest as a proof that there are distinct strains of the disease.

But Dr. Moyano noted that prion strains are characterized not just by differential incubation times but also by a distinctive neuropathology (either different target cells or brain areas), and biochemical differences that correspond with different conformations.

Therefore the transgenic “neutral” mice, while a good model for studying progression of transmitted disease, “do not allow one to conclude something definitive about strain specificity as there is no expression of alpha-synuclein in the oligodendrocytes (major target cells in MSA) and the neuropathological features,” she explained.

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•. Watts J, Giles K, Prusiner SB, et al. Transmission of multiple system atrophy prions to transgenic mice. Proc Natl Acad Sci USA; E-pub 2013 Nov. 11.
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            © 2013 American Academy of Neurology