December 2, 2021

I, Science

The science magazine of Imperial College

Rapidly multiplying misfolded proteins undetected by the human immune system - Sophia Ho explains why prions are important in understanding diseases.

brain  Allan Ajifo 14599057094_8e82e0e482_b_2Creutzfeldt-Jakob Disease, Kuru, Fatal Familial Insomnia – in what may seem like a list of ruthless and incurable neurodegenerative diseases lies a littler known, yet remarkable phenomenon: the prion.

Prions are not bacteria, viruses, parasites or even fungi. They don’t result from malfunctioning immune systems. Yet they are extraordinary as they can be propagated through three very different modes of disease transmission; they can be inherited, spread via contaminated materials, or simply occur spontaneously.

But what is this mysteriously unstoppable prion, which can cause convulsions, behavioural changes, loss of coordination and dementia, often followed by fatality within months of onset?

The prion, whose name comes from a bizarre combination of the words ‘protein’ and ‘infection’, is merely the misfolded form of a normal protein known as PrPC, which is found throughout the body and is responsible for attachment and cell signalling. Proteins exist in unique shapes which are essential for their function, therefore the loss of this shape can make it lose its function, or even become toxic to the cell. This forms the basis of many disorders, including those listed above and others such as Alzheimer’s and Huntington’s disease.

Prion Structure AJ Cann 464066753_47a5db5113_o
Abnormal and normal folding of prion protein

Prions, however, differ hugely from other misfolded proteins in their ability to self-propagate and multiply. As prions are not living structures, they are often compared with viruses. However, this assumption is incorrect, as unlike viruses, genetic material is not necessary for their function or spread (excluding the inherited forms causing 10-15% of all prion disease).

How then, does a prion come about? How can it spread if there’s no genetic material to replicate? Even now scientists can only hypothesise the processes underlying prion diseases.

For hereditary forms at least, such as Fatal Familial Insomnia, it has been established that mutations in the PRNP gene lead to prion proteins that are more likely to fold abnormally. For sporadic and transmissible forms, the cause is still a mystery. However, it is known that the shape of any protein can be affected by changes in its environment, such as temperature or acidity, causing the unfolding of a protein to an unstable form.

The unstable form of prion, known as PrPSc, tends to clump, or aggregate, with regular PrPC proteins. In doing so, it causes these to convert to PrPSc at an exponential rate, leading to a fatal chain reaction.

Studies have suggested that the immune system not only tolerates this dangerous difference, but may even unknowingly aid their spread throughout the nervous system and brain, where aggregation fatally occurs.

This aggregation destroys tissue and creates plaques that eventually form holes in the brain itself, leaving it a ‘sponge-like’ structure. It may be appropriate then that prion diseases are known as spongiform encephalopathies (SEs).

VCJD_Tonsil Wikipedia
Immunostaining of prion protein in a tonsil biopsy in variant CJD.

SEs are famously associated with cannibalism practised by tribes in Papua New Guinea, leading to Kuru, and the feeding of cattle meat to other cattle, which led to the outbreak of Creutzfeldt-Jakob Disease (CJD) in the UK in 1986. This resulted in the deaths of 166 people, and the infection and culling of 4.4 million cattle. In 2013, it was estimated that 1 in 2,000 people in the UK still carry the CJD-causing prion (which may continue conversion without symptoms for decades).

CJD is of continual global concern. As recently as September 2013, Russia finally lifted its 26-year ban on British beef imports. Many countries also ban blood donations from individuals who have lived for at least three months in the UK between 1980 and 1996, or at least five years in any European countries from 1980 until now.

Promising diagnostic and therapeutic measures are continually being developed to detect and prevent PrPSc accumulation. Nonetheless, it is astonishing that the cause behind such harrowing and terrifying disorders is a simple error, with no seeming cause at all.

Sophia Ho is studying for an MSc in Molecular Medicine

Images:  Brain by Allan Ajifo /; Prion Structure by AJ Cann; Prion staining in CJD Wikipedia