Prions: Could these zombie-like proteins be responsible for causing the most common form of Dementia?

Post courtesy of Dr Michael Chan, PGY2 Medicine Resident, Monmouth Medical Center.

ImageAs far as infectious diseases go, prions are a relatively new discovery. While humanity has known about parasites since ancient times, bacteria since the 1660s, and viruses since 1898, the first prion protein was only isolated in 1984. Since then, we’ve gotten to know a little more about these proteins, and we’ve found that its novelty is by no means the most interesting thing about it.
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So what are prions?

Prions are basically the misfolded version of a normal protein, PRP or Protease resistant protein. In the vast majority of instances, the body has mechanisms that adequately deal with misshapen proteins. These get tagged for destruction by antibodies or intracellularly by specific molecular signals and lysosomes. However, prions are not your run of the mill abnormal protein. They are resistant to degradation and exhibit the unique characteristic of causing other normal PRP proteins to misfold, which in turn causes even more misfolding. In this sense, prions behave like protein zombies.

And like zombies, they don’t begin their existence as malevolent molecules either. Indeed this is one of the characteristics which differentiate prions from most other infectious agents such as bacteria or viruses, majority of which are inherently disease causing. Studies have shown that normal PRP has functions in sleep, memory, neural development, and possibly the maintenance of the myelin sheath that surrounds neurons. Indeed, a mutation of PRP causes a very rare disease (only 8 cases have been diagnosed as of 2005) called Familial Fatal Insomnia which leads to progressively worse insomnia leading to dementia, hallucinations, and eventually death.

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Yes, complete inability to sleep kills.


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The connection to Alzheimer’s

Until recently, the most notable examples of prion diseases in humans are Creutzfeldt-Jakob disease and Kuru. Although spontaneous CJD does rarely occur, both these diseases are usually caused by ingestion of infected material, ie, eating infected meat (beef) for CJD and cannibalism for Kuru. Both exhibit progressive dementia, memory problems, gait and movement disturbances, and other unusual symptoms like uncontrolled laughter, hallucinations, and personality changes. Pathologically, the disease causes patients’ brains to develop tiny holes, much like a sponge. Thus the name for the disease in cows, Bovine Spongiform Encephalopathy, literally translates “cow spongy brain disease”.

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Brain of a CJD patient with multiple “holes”

However, over the past 5 years, research has shown that at least one major protein known to accumulate in Alzheimers disease, amyloid beta, behaves much like prions. Research conducted at UCSF showed that when mice brains are seeded with amyloid beta, after 300 days, the amyloid plaque is found all over the brain, not just the area seeded. A Yale university study in 2009 also showed that prion proteins of CJD interact with amyloid beta in some way to cause the dysfunction in neurons which lead to Alzheimer’s. Although there is no evidence that AD is contagious, it may open up new therapeutic avenues to think of its pathology as like that of prion diseases.

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Amyloid plaques and Neurofibrillary tangles in Alzheimer’s disease

How Alzheimer’s spreads in the brain.

Indeed, last year, a British team accidentally stumbled on a discovery that antibodies designed to treat CJD were found to block Alzheimer’s disease. These antibodies, ICSM-35 and ICSM-18, blocked the interaction between the PRP prion and amyloid beta in mice brains, resulting in decreased hippocampal nerve cell disruption. ICSM-18 and ICSM-35 are presently undergoing human trials for the treatment of CJD. With this finding, it’s likely they will be tested for Alzheimer’s as well, and we, for the first time, might have an effective and specific treatment for this disease which affects roughly 20 million people worldwide.

To see just how significant any form of treatment might be, check out the facts and figures provided by http://www.alz.org below:

References:

Jucker M, Walker LC. Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. 2011:70, 532–540.

Prusiner SB: A unifying role for prions in neurodegenerative diseases. 2012:336, 1511–1513.

Freir DB, Nicoll AJ, Klyubin I et alInteraction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sitesNature Communications, June 7 2011

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