Prions and their shadow proteins: an interview with Dr Jiri Safar, Co-Director of the National Prion Disease Pathology Surveillance Center

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Please can you give a brief introduction to prions and the neurodegenerative diseases they cause?

The prion diseases were originally discovered by Dr Gajdusek and Dr Gibbs. The first disease discovered was Kuru, which was affecting native tribes in the Papua New Guinea highlands in the 1950s.

Gajdusek and Gibbs showed that the pathology of Kuru was not dissimilar to that seen in other neurodegenerative diseases such as Alzheimer’s. However, the difference was that the prions in Kuru were actually transmissible and had probably been transmitted as a result of the cannibalism rituals the tribes used to perform. On realizing this, the Australian government were able to convince the tribe leaders to stop the practice, which they seemed to do.

We know Kuru came from those areas and also that prion diseases have a very long incubation period, because some patients that were exposed to the disease in the 1950's only developed symptoms after 50 years.

What was previously known about the mechanism by which normal prion proteins are converted into the diseased form?

The mechanism is still undergoing very intense investigation. We know that the normal and abnormal proteins have to meet on the surface of the cell that they enter. However, the molecular mechanism that follows, how the abnormally folded protein is able to convert the normal folded protein to an abnormal form, is still not clear.

There is a lot of very intense effort to understand the principles because we think that a similar mechanism may be responsible for propagating the pathology of other neurodegenerative diseases such as Alzheimer's, Parkinson's and amyotrophic lateral sclerosis.

How do the rates of replication of test tube prions differ from those in vivo?

We know in human prion diseases, that the incubation time can be very long. If you amplify prions in a test tube, however, within days or weeks they can amplify to the same degree that is seen in the brains of patients with end-stage prion disease.

There is a huge discrepancy between the very fast speed at which the prions replicate in the test tube and the incubation time seen in humans.

Please can you outline how your study investigated the molecular puzzle of the long asymptomatic time period?

I think that the greatest difficulty until now has been that most of the data on the normal protein, which is effectively the precursor to the infectious prion, has come from investigating DNA and RNA.

If you look at the DNA and RNA, there are no changes which would indicate any up- or down-regulation of the normal protein, which has led to people assuming that the normal prion protein is staying the same.

The problem is that the only difference between the abnormal and normal proteins is the shape. The amino acid sequence and post-translational modifications are the same and on a standard western blot, they cannot really be differentiated.

In the last several years, we have developed a technique which allows us to separate out the normal protein from the infectious prions. Using this technology, we measured levels of the normal precursor protein and abnormal protein in mouse and hamster models and found, surprisingly, that the normal prion protein actually dropped about halfway through the incubation time of the disease, long before symptoms actually develop.

This would explain why the incubation time is so long. If the substrate which enables the conversion to abnormal protein is taken out, as well as the receptor for the toxicity of the prion, you have two different mechanisms which prolong the disease's silent incubation time.

Your study looked at the ‘shadow of the prion protein’. Please can you explain what this molecule is and why it was of interest?

That is what we call a prion protein parallel, which means it is upstream of the protein prion gene but doesn’t have the same sequence, despite having similar conformational characteristics.

This was discovered in Australia using computation and informatics tools and later, it was actually found expressed in the brain by Dr. David Westaway, my collaborator at the University of Alberta, Canada.

When David measured the protein, he found out quite early on that it was dropping. We then asked ourselves what happens with the normal prion protein and we found this down-regulation effect caused by prion infection.

What are the main results of your research and what impact do you think they will have?

I think that the main result is that we found this down-regulation, which effectively indicates that the cells are somehow able to discriminate the normal proteins from the abnormal ones. Once the cells sense the abnormal prion, they down-regulate normal prion proteins, meaning diminished levels are expressed on the cell surface.

This will imply a very new mechanism regarding the protein regulation at the cellular level, a mechanism that does not involve the usual DNA/RNA machinery and is effectively all happening after the translation process. This post-translational process is really important because it may dramatically affect the disease duration. If we could understand exactly what the mechanism is, we could help cells effectively “turn down” the prion infection in the long term.

In addition, we suspect that a similar mechanism may also exist in other neurodegenerative diseases with long incubation times such as Alzheimer's and Parkinson's. We would like to look into those diseases and see if we can identify a similar effect. With the use of pharmacological interventions or other tools, we should be able to extend the asymptomatic stage of the disease or eventually stop the disease completely.

What research still needs to be done to increase our understanding of prions and the diseases they cause?

I think that we need to concentrate on the normal prion proteins – how the normal prion protein is regulated and, specifically, how it is down regulated. If we can understand this mechanism, we can seek interventions.

One way would be to use the small, inhibitory RNA which could effectively turn down the normal prion protein expression. However, we need a better understanding of this down-regulation mechanism before we can start thinking about therapeutic interventions.

Do you think it will one day be possible to prevent prion disorders by treating patients in the pre-clinical phase before they show symptoms?

Yes, that is the ultimate goal.

Where can readers find more information?

About Dr Jiri Safar

Jiri G. Safar, MD, is an Associate Professor in the Departments of Pathology and Neurology and Co-Director of the National Prion Disease Pathology Surveillance Center (NPDPSC) at Case Western Reserve University School of Medicine. An internationally renowned neuroscientist and biochemist with more than 25 years in the prion field, he is a leader in research on neurodegenerative diseases caused by protein misfolding, such as Creutzfeldt-Jakob Disease (CJD), mad cow disease (BSE), Alzheimer's disease (AD), and Parkinsonism.

Dr. Safar holds 27 patents, including one for a method to detect misfolded proteins and another for a device that removes prions from blood, plasma and other liquids. His international stature is firmly established. He served on the British Spongiform Encephalopathy Advisory Committee from 1999 to 2003; is a member of the European Union's Prion Expert Group; and a member of the World Health Organization's Advisory Board for Prion Diseases. He is the author of more than 188 publications, encompassing a broad range of research in conformational protein chemistry, molecular biology, immunology, and neurodegeneration in human and animal prion diseases. His 1998 Nature Medicine paper is the most quoted original work published on prions in the past 16 years – cited 740 times.

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April Cashin-Garbutt

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April Cashin-Garbutt

April graduated with a first-class honours degree in Natural Sciences from Pembroke College, University of Cambridge. During her time as Editor-in-Chief, News-Medical (2012-2017), she kickstarted the content production process and helped to grow the website readership to over 60 million visitors per year. Through interviewing global thought leaders in medicine and life sciences, including Nobel laureates, April developed a passion for neuroscience and now works at the Sainsbury Wellcome Centre for Neural Circuits and Behaviour, located within UCL.


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