New Type of Prion May Cause And/Or Transmit Rare But Fatal Brain Disorder

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by Charles Moore |

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According to two new research papers led by University of California at San Francisco (UCSF) scientists, Multiple System Atrophy (MSA), a progressive neurodegenerative disorder with similarities to Parkinson’s disease, is caused by a newly discovered type of prion, a variant of the misfolded proteins associated with incurable progressive brain diseases such Creutzfeldt-Jakob Disease (CJD or “mad cow disease”), that may be transmissible on contact.

First described in 1960, MSA is described by the National Institute of Neurological Disorders and Stroke as characterized by a combination of symptoms that affect both the autonomic nervous system (the part of the nervous system that controls involuntary action such as blood pressure or digestion) and movement. Rare but more common than CJD: MSA annually affects three out of 100,000 people over the age of 50, Symptoms of MSA reflect progressive loss of function and death of different types of nerve cells in the brain and spinal cord, with early-stage symptoms that can be mistaken for those of Parkinson’s disease, including movement and balance problems, loss of bladder control, and disruption of blood-pressure regulation and other functions governed by the autonomic nervous system. However, unlike Parkinson’s patients, who often live 10 to 20 years after being diagnosed, MSA patients typically die within five to 10 years and do not respond to the drugs or deep brain stimulation used for Parkinson’s symptoms.

The UCSF researchers’ findings suggest new approaches to developing treatments for MSA, for which there are currently no treatments to delay the progressive neurodegeneration and no cure, but also highlights a potential concern for clinicians or scientists who come in contact with MSA tissue.

A UCSF release authored by freelance science writer Nicholas Weiler notes that the new findings mark the first discovery of a human disease caused by a new prion in 50 years, since work at the National Institutes of Health in the 1960s showed that human brain tissue infected with CJD could transmit neurodegeneration to chimpanzees.
In 1982 UCSF professor of neurology and biochemistry Stanley Prusiner, MD, discovered an unprecedented class of pathogens that he named prions — “infectious proteins” — that cause neurodegenerative diseases in animals and humans. Dr. Prusiner found that prions were the causative agent for a brain-wasting disease found in sheep called scrapie, subsequently determining that the same prion protein caused bovine spongiform encephalopathy (BSE), or “mad cow” disease, in cattle, and so-called “variant” Creutzfeldt-Jakob Disease in humans who had consumed BSE-contaminated beef or other animal tissues. that manifest as (1) sporadic, (2) inherited and (3) infectious illnesses.

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When proposed, many scientists considered Dr. Prusiner’s concept of “infectious proteins” as well as his proposal that a a simple protein could possess multiple biologically active shapes or conformations and replicate and spread disease to be “heretical,” contradicting as it did a tenet of modern biology that maintained only viruses and living microbes such as bacteria had the capacity to transmit disease. However subsequent research by Dr. Prusiner and others led to better understanding of how prions function at a molecular level, and Dr. Prusiner was awarded the Nobel Prize in Physiology or Medicine for this work in 1997, for his discovery that these self-replicating misfolded proteins cause Creutzfeld-Jakob Disease and other related forms of neurodegeneration.

Dr. Prusiner is now director of the Institute for Neurodegenerative Diseases at UCSF, and his contributions to scientific research have also been internationally recognized with numerous other prizes including the Potamkin Prize for Alzheimer’s Disease Research from the American Academy of Neurology (1991); the Richard Lounsbery Award for Extraordinary Scientific Research in Biology and Medicine from the National Academy of Sciences (1993); the Gairdner Foundation International Award (1993); the Albert Lasker Award for Basic Medical Research (1994); the Wolf Prize in Medicine from the State of Israel (1996); and the United States Presidential National Medal of Science (2009). He is a member of the National Academy of Sciences, the Institute of Medicine, the American Academy of Arts and Sciences and the American Philosophical Society, and a foreign member of the Royal Society, London.

Based on his seminal discovery that prions can assemble into amyloid fibrils — peptide or protein aggregates which assemble to form insoluble fibers that are resistant to degradation, plaques of which are found in brain tissue of Alzheimer patients and are associated with neurodegeneration, Dr. Prusiner proposed that the more common neurodegenerative diseases including Alzheimers and Parkinsons diseases may be caused by prions, with evidence continuing to accumulate that prions cause not only these common degenerative diseases, but also Amyotrophic Lateral Sclerosis (ALS, or Lou Gehrig’s Disease) the frontotemporal dementias (FTDs), chronic traumatic encephalopathy (CTE) and multiple system atrophy (MSA). Much of Dr. Prusiner’s current research is focused on developing therapeutics that reduce the levels of the specific prions responsible for Alzheimer’s, Parkinson’s, MSA, the FTDs, CTE and CJD.

GIlesK“Now we’ve conclusively shown that a new type of prion causes MSA,” UCSF’s Kurt Giles, DPhil, associate professor of neurology, IND researcher and senior author on the second of the two new studies tells Mr. Weiler in the UCSF release. “This is our mark in the sand.”

Mr. Weiler notes that, the original prion protein identified by Dr. Prusiner as being responsible for CJD, known as PrP, can exist in two forms: one of which harmless and the other fatal. PrP prions in the dangerous, misfolded form latch on to other nearby PrP molecules, causing them to lose their normal shape and initiating a chain reaction that results in sticky, insoluble plaques throughout the brain that kill off cells and result in the typical “spongy” appearance of CJD-affected brains — hence the designation “spongiform”.

In the new research papers, published the weeks of Aug. 17 and Aug. 31, in the Proceedings of the National Academy of Sciences, Prusiner, Giles, post-doctoral researcher Amanda Woerman, PhD, and an international team of colleagues report that a misfolded version of a protein called alpha-synuclein seems to act in a similar way to transmit MSA from diseased human brain tissue to mice and to human cell cultures.

A new research paper published in the journal Proceedings of the National Academy of Sciences, entitled “Evidence for a-synuclein prions causing multiple system atrophy in humans with parkinsonism” (Published online before print PNAS August 31, 2015, doi: 10.1073/pnas.1514475112), coauthored by Dr. Prusinera with an international team of investigators including researchers from UCSF; Daiichi Sankyo Co., Ltd.; the University of Texas Southwestern Medical Center; Imperial College London; Massachusetts General Hospital; Stanford University; UC Los Angeles, and the University of New South Wales. describes how experiments conducted in Dr. Prusiner’s lab in 2013 revealed that samples of brain tissue from two human MSA patients were able to transmit the disease to a mouse model for Parkinson’s disease, expressing a mutant human alpha-synuclein gene. To confirm this finding, Prusiner and colleagues expanded this experiment to include tissue samples from a dozen more MSA victims from tissue banks on three continents: the Massachusetts Alzheimer’s Disease Research Center in Boston, the Parkinson’s UK Brain Bank at Imperial College London, and the Sydney Brain Bank in Australia.

The coauthors note that MSA is caused by a different human prion composed of the -synuclein protein, and while brain extracts from Parkinson’s disease (PD) patients have not been found to be transmissible to genetically engineered cells or mice, they’ve discovered that -synuclein prions that cause the more common MSA), but that brain extracts from 14 MSA cases all transmitted neurodegeneration to mice. When exposed to human MSA tissue, the mice developed neurodegeneration. In addition, the team found that the brains of infected mice contained abnormally high levels of insoluble human alpha-synuclein, and that infected mouse brain tissue could itself spread the disease to other mice, observing that -synuclein is the first new human prion to be identified, to the investigators’ knowledge, since the discovery a half century ago that CJD was transmissible.

Mr. Weiler notes that the discovery that alpha-synuclein prions can transmit MSA raises a public health concern regarding treatments and research that involve contact with brain tissue from neurodegeneration patients, because standard disinfection techniques that kill microbes do not eliminate the PrP prions that cause CJD, although whether the same challenges hold for alpha-synuclein prions in MSA remains to be determined.

In the meantime, PNAS paper’s coauthors advise that clinicians and researchers should adopt much more stringent safety protocols when dealing with tissue from patients with MSA and other neurodegenerative diseases, many of which they believe may also be caused by prions. For instance, MSA is frequently initially misdiagnosed as Parkinson’s disease, which is often treated with deep-brain stimulation with potential for the disease to be transmitted to other patients if deep-brain stimulation equipment is reused, even with standard sterilization protocols in place.

“You can’t kill a protein,” Dr. Giles observes in the release. “And it can stick tightly to stainless steel, even when the surgical instrument is cleaned.” As a result, he said, “We’re advocating a precautionary approach. People are living longer and likely getting more brain surgeries. There could be undiagnosed neurodegenerative diseases that – if they’re caused by prions – mean infection could be a real worry.”

However, unlike the danger of BSE from contaminated beef, the researchers stress that there is no apparent risk of infection by MSA prions outside of specialized medical or research settings.

woermanaIn another PNAS paper published earlier in August entitled “Propagation of prions causing synucleinopathies in cultured cells” (PNAS August 18, 2015 Published online before print doi: 10.1073/pnas.1513426112), Dr. Amanda L. Woerman of the UCSF Institute for Neurodegenerative Diseases led a research team in development of a rapid new method to test prion transmission using human cell cultures, and was able to demonstrate that it only takes four days for human MSA tissue to infect cultured cells with alpha-synuclein mutations, in contrast to the 120 days it takes for the disease to spread to mouse models. The investigators conclude: “Our studies should facilitate investigations of the pathogenesis of both tau and a-synuclein prion disorders as well as help decipher the basic biology of those prions that attack the CNS.”

“The challenge of studying neurodegeneration is that it’s a disease of aging,” Dr. Woerman told Mr. Weiler. “You have to let the mouse models develop for such a long time that research on cures is really slow to progress. Now, with these cell models, we can test how to inactivate alpha-synuclein aggregates at a speed that just wouldn’t be feasible in animals.”

Mr. Weiler notes that the UCSF researchers are working with Japanese pharmaceutical company Daiichi Sankyo, as part of a collaboration established in 2014 to develop potential treatments for prion diseases.

Major funding for this research was provided by grants from the National Institutes of Health and gifts from the Sherman Fairchild Foundation and Mary Jane Brinton.

University of California at San Francisco (UCSF)
UCSF Institute for Neurodegenerative Diseases
Proceedings of the National Academy of Sciences
National Institute of Neurological Disorders and Stroke

Image Credits:
UCSF Institute for Neurodegenerative Diseases

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