Cellular Prions, Their Possible Functions & What happens when they go bad

1.1 Introduction to Prions

Prions are a type of glycoprotein encoded by the Prnp gene1 found predominantly in the brain and central nervous system, but can also be located outside of this area in mammals. There are two isoforms: infectious scrapie (PrPSC) and cellular (PrPC). The cellular prion is a host encoded glycoprotein found anchored in the membrane of cells. Cellular prions have the ability to change their structural composition to have a higher percentage of beta sheets as seen in the infectious form2. These infectious prions aggregate together and cause problems disrupting important functions such as neuronal survival.The infectious prion protein is resistant to denaturation either by heat or enzymatically3. They are also transmissible amongst different mammals4. These infectious prions are thought to be the cause of various neurodegenerative diseases such as Creutzfeldt-Jakob disease and Kuru. The majority of prion diseases are sporadic, but they can also be hereditary and acquired5.

The function of cellular prions have yet to be determined. However there have been many studies that show there are some relationships between these proteins and other important functions. There is evidence to show that cellular prions have the ability to promote neurogenesis in addition to slowing down the rate of neurodegeneration in the brain. Furthermore, endogenous cellular prions may be able to protect the brain from neurodegenerative diseases caused by infectious prions. Once we understand the function of cellular prion protein, it may provide insight into other mechanisms for neurodegenerative diseases, which could potentially lead to cures and better treatments. Currently, there are no cures for human transmissible spongiform encephalopathies, also known as infectious prion diseases.

1.2 Proposed Mechanisms of PrPC turning into PrPSC

There are several proposed mechanisms and models such as the prion hypothesis, nucleation dependent aggregation mechanism, cooperative autocatalysis model and the heterodimer mechanism.

1.2a Prion Hypothesis

In the prion hypothesis, the infectious prion induces changes by interacting with the cellular prion turning it into the infectious form. This infectious isoform then goes on to induce these changes in other healthy cellular prions where they can then aggregate together6. This process slowly transforms the cellular prions into infectious proteinacious agents which cause severe neurodegenerative diseases.

1.2b Nucleation Dependent Aggregation Mechanism

The nucleation dependent aggregation mechanism7 explains the infectious prions replication to occur through using the monomers of cellular prions, and combining them into an aggregated structure. Through the interactions between these two types of glycoproteins, the PrPC will then adapt the structure of the PrPSC by having many more beta sheets than alpha helices. These aggregates grow by continually taking cellular prion monomers and changing them into infectious conformations so that they can spread and make aggregates with other PrPC.

This picture was used to show how the monomers come together and form the beta sheet rich aggregates. These aggregates are resistant to degradation by SDS and other techniques.

1.2c Cooperative Autocatalysis Model

The cooperative autocatalysis model explains prion replication occurs when the cellular and infectious prions form aggregates2 , but with allosteric interactions thus inducing the conformational change7. This model proposes that this is the mechanism which induces change in the structural composition of the PrPC.

1.2d Heterodimer Model

Unlike these other mechanisms, the formation of a prion aggregate is not required for the heterodimer model7 to occur. This model states that when one cellular prion and one infectious prion interact by forming a heterodimer, the cellular prion changes it conformation to take on that of the infectious prion.‍‍

Possible Functions

The function of cellular prion proteins have yet to be discovered however there have been many studies conducted showing they play important roles in the brain. When these proteins change their conformation into the PrPSC isoform, this causes neuronal degeneration which can lead to serious neurological diseases. Possible functions of host encoded cellular prion protein include having neuroprotective effects against neuronal cell death, promoting neurogenesis, and delaying the onset and reducing the severity of the symptoms in neurodegenerative diseases such as Amyotrophic Lateral Sclerosis.

1.3 Cellular prions may promote neurogenesis and prolong cell survival 8

In the central nervous system, cellular prion proteins are found in astrocytes and neurons. There has been evidence showing that they prolong the survival9 as well as affect the differentiation of these structures. Scientists have found that cellular prions interact with NCAM, neuronal cell adhesion molecules, in astrocytes and this causes neurogenesis. Another role that the cellular prions might be involved in is the differentiation process of neurons. Scientists have found that when the ligand, STI1 (secreted from astrocytes) binds a receptor on the cellular prion glycoprotein membrane, the neurons differentiate. There were much lower levels of neurogenesis in neuron-astrocyte co-cultures, when they did not express the Prnp gene. Furthermore, they suggested that the interaction between cellular prion proteins and STI1 may play a role in protecting against apoptosis, as they have seen in neurons located in the hippocampus and the retina8 . It is likely that there are other molecular factors in conjunction to NCAM and STI1 that may be important for the survival and differentiation processes of neurons.
A picture of GFAP stained astrocytes take from houseofmind.tumblr.com

1.4 Cellular prions, anchored or not, prevent neurodegeneration10

1.4a Results with a mutated PrPC compared to host encoded PrPC

Cellular prions have been shown to have the ability to protect mammals from neurodegenerative diseases. The group that found this result created transgenic mice expressing a truncated prion protein lacking residues 32-134. With the expression of the truncated prion protein, tremors and wobbly gait developed in these mice very early in on in the experiment. The symptoms worsened quickly with hind limb paralysis and muscle wasting becoming more apparent as time progressed. When the wildtype mouse prion protein was also expressed along with the truncated prion protein, they did not observe these severe neurological symptoms. They inferred that the presence of cellular prion proteins is what provided the added protection against the effects of the truncated cellular prions.

In this same experiment they made transgenic mice that expressed the wildtype hamster prion as well as the truncated mouse prion to see the effects in different cells in the central nervous system. They found those that expressed the wildtype hamster prion protein showed similar positive effects as the wildtype mouse prion. They came to this conclusion since they protected cells from being infected with diseases. The wildtype hamster prion in conjunction with the truncated mouse prion prolonged cell survival to over 400 days in different types of cells like neurons and astrocytes in the central nervous system.

1.4b Soluble Prion Protein10

They also looked at transgenic mice expressing soluble prion proteins and whether being anchored and restricted to one site could yield the same protective effects as being anchorless and able to float through the extracellular fluid to different sites. They found that there was a longer life span of 100 days with the mice that expressed the soluble prion, in comparison to those that expressed the anchored, truncated prion. However, this result of prolonged cell survival did not compare to the life spans of those cells that express the wildtype prion protein, as they were much longer. From this evidence, it has been shown that whether the prion is anchored or not, it can have a protective effect against the process of neurodegeneration.

1.5 Cellular prions may protect against Amyotrophic Lateral Sclerosis (ALS)11

Steinacker et al. found in transgenic mice that suffered from Amyotrophic Lateral Sclerosis, the host encoded cellular prion protein, may serve as protection from oxidation for neurons and glia. They used mice that expressed a mutated SOD1, superoxide dismutase 1 gene, to mimick the effect of Amyotrophic Lateral Sclerosis. Then they took these mice, and crossed them with mice that expressed the Prnp gene and ones that did not. They observed that the mice that had Amyotrophic Lateral Sclerosis and lacked the cellular prion proteins showed earlier onset of this disease when compared to the mice that expressed this protein. Also these Prnp null mice had lower body weights and less spinal cord motor neurons. Another trait that was observed was their performance on the Rotarod Performance test was very poor. The Rotarod Performance test12 is a test that measures the motor skills of mice and is very useful in detecting damage or impairments associated with the cerebellum, the region of the brain responsible for motor control.

They showed that those mice that lacked the cellular prion protein had suffered more severe symptoms in the early stages of the disease. In comparison to these mice, those that expressed the wildtype cellular prion protein had a longer life span, with less neurodegeneration, later onset of disease symptoms with less severity. Scientists hypothesized that protection against oxidation could be an important role of the cellular prions. Their results proved this to be correct since this result is what they observed in cell culture. Cellular prions protect astrocytes, helps them control the amount of secreted factors and stimulates the production of new neurons as well as aid in prolonging their survival. These cellular prion proteins have shown to be a very important component in Amyotrophic Lateral Sclerosis, because they resulted in a later onset of the disease symptoms and decreased the rate of progression when compared to those mice that lack the prion protein.

1.6 Human Transmissible Spongiform Encephalopathies

Infectious prion diseases occur when the normal cellular prion protein becomes misfolded. There are many mechanisms that provide an explanation of how these proteins can change their conformation. When they do this it can cause serious, rare, neurodegenerative diseases in the brain such as Creutzfeldt-Jakob disease, Kuru, Gerstmann-Sträussler-Scheinker disease, fatal Familial Insomnia, and variant Creutzfeldt-Jakob disease. There are currently no cures for these transmissible spongiform encephalopathies. However, there are new tools being designed to better treat people who suffer from these diseases. One tool that just came out last year was the Creutzfeldt-Jakob disease Neurological Scale13. It can be used to measure the level of degeneration in the brains’ of those who suffer from Creutzfeldt-Jakob disease.

This picture was taken from health.allrefer.com. This is a picture showing some typical characteristics of Creudfeldt-Jakob disease. These are also commonly seen in other transmissible spongiform encephalopathies caused by infectious prions.

1.6a Kuru

Kuru was the first transmissible disease that was known to be severely damaging to the human central nervous system. Its discovery was in Papua New Guinea. As part of the tribal culture, the act of cannibalism was a common ritual practiced when there was a death of a relative14. It was thought that this was how Kuru was transmitted. However now it has been shown that, like other prion diseases, it has some genetic links, can occur sporadically in addition to it being acquired15. It clinically manifests by cerebellar ataxic syndrome with increasing loss of motor function and weakening as the disease progresses. Those afflicted by Kuru experience euphoria, extreme laughter as well as other emotional disturbances such as depression. Kuru kills very quickly with people dying, on average, after 1 year14.

Image taken from musee-afrappier.qc.ca. This shows two tribal people eating the brain of a deceased relative. This was how scientist previously thought people acquired Kuru.


1 .Vanderperre, B. et al. An overlapping reading frame in the PRNP gene encodes a novel polypeptide distinct from the prion protein. FASEB journal 25, 2373-2386 (2011).
2. Małolepsza, E., Boniecki, M., Kolinski, A., Piela, L. & Levitt, M. Theoretical Model of Prion Propagation: A Misfolded Protein Induces Misfolding. PNAS 102, 7835-7840 (2005).
3. Kuczius, T., Wohlers, J., Karch, H. & Groschup M. H. Subtyping of human cellular prion proteins and their differential solubility. Experimental Neurology 227, 188-194 (2011).
4. Adriano, A. et al. A molecular switch controls interspecies prion disease transmission in mice. Journal of Clinical Investigation 120, 2590-2599 (2010).
5. Shkundina, I. & Ter Avanesyan, M. Prions. Biochemistry (Moscow) 72, 1519-1536 (2007).
6. Karim, A., Rodrigo, M. & Claudio, S. Cellular factors implicated in prion replication. Elsevier 584, 2409-2414 (2010).
7. Rubenstein, R. et al. Dynamics of the nucleated polymerization model of prion replication. Biophys Chem 125, 360-7 (2007).
8. Lima, Flavia R S et al. Cellular prion protein expression in astrocytes modulates neuronal survival and differentiation. Journal of Neurochemistry 103, 2164-2176 (2007).
9. Satoh, J. et al. Protein microarray analysis identifies human cellular prion protein interactors. Neuropathology and Applied Neurobiology 35, 16-35 (2009).
10. Race, Brent. et al. Prion protein on astrocytes or in extracellular fluid impedes neurodegeneration induced by truncated prion protein. Experimental Neurology 217, 347-352 (2009).
11. Steinacker, P. et al. Neuroprotective Function of Cellular Prion Protein in a Mouse Model of Amyotrophic Lateral Sclerosis.The American Journal of Pathology 176, 1409-1420 (2010).
12. Hiromi, S. et al. A rotarod test for evaluation of motor skill learning. Journal of Neuroscience
Methods 189, 180-185 (2010).
13. Cohen, O. S. et al. The Creutzfeldt–Jakob disease (CJD) neurological status scale: a new tool for evaluation of disease severity and progression. Acta Neurologica Scandinavica 124, 368-374 (2011).
14. Liberski, P. et al. Kuru: Genes, Cannibals and Neuropathology. Journal of Neuropathology & Experimental Neurology 7, 92-103 (2012).
15. Mead, S. et al. Genetic Susceptibility, Evolution and the Kuru Epidemic. Phil. Trans. R. Soc. B 363, 3741-3746 (2008).

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