Prions: Misfolded Proteins That Spread

Most infectious diseases are caused by something that carries genes — bacteria, viruses, fungi, parasites. Prions are the strange exception. A prion is an infectious agent made of protein alone, with no DNA or RNA. It causes disease by changing its shape and forcing normal copies of the same protein to adopt that shape too. The idea was so surprising that it was resisted for years, but it’s now well established, and it has transformed how we think about protein folding and several brain diseases.

The diseases

Prion diseases, also called transmissible spongiform encephalopathies (TSEs), affect the brain. They’re rare but invariably fatal, and they share features:

• a long incubation period, often years or decades
• rapid decline once symptoms appear: problems with movement, memory and behaviour
• a sponge-like appearance of brain tissue under the microscope, with many small holes where nerve cells have died
• no inflammation or immune response, because the agent is the body’s own protein

Examples include:

Disease	Host	Notes
Scrapie	Sheep, goats	Known for centuries
BSE (“mad cow disease”)	Cattle	Epidemic in the UK in the 1980s–1990s
Chronic wasting disease	Deer, elk, moose	Spreading in North America and elsewhere
Creutzfeldt–Jakob disease (CJD)	Humans	Mostly sporadic; about 1–2 cases per million people per year
Variant CJD (vCJD)	Humans	Linked to eating BSE-contaminated beef
Kuru	Humans	Spread by funeral practices in Papua New Guinea; now essentially gone

The protein: PrP

All mammals make a normal protein called the prion protein, PrP. It’s found on the surface of many cells, especially nerve cells, anchored to the outer membrane. Its normal function is still debated; it may be involved in copper binding, protecting nerve cells and maintaining myelin.

The normal form is called PrP^C (“cellular”). The disease-causing form is PrP^Sc (“scrapie”). The crucial point: both have exactly the same amino acid sequence. They differ only in how the chain is folded.

Two shapes, one sequence

The normal protein, PrP^C, has a flexible, disordered tail and a folded, globular region containing three α-helices and only a small, two-stranded β-sheet. It’s soluble and is broken down normally by the cell’s protein-digesting enzymes.

The misfolded form, PrP^Sc, is rich in β-sheet structure. Chains line up side by side, held by hydrogen bonds between their backbones, forming long stacks. These properties follow:

Property	PrP^C (normal)	PrP^Sc (prion)
Main secondary structure	α-helices	β-sheets
Solubility	Soluble	Insoluble; forms aggregates
Digestion by proteases	Fully digested	Partly resistant
Tendency to aggregate	Low	Forms fibrils and plaques
Infectious?	No	Yes

This is a striking example of the principle that shape determines function (see protein folding). Normally, a protein’s sequence determines one stable fold. PrP shows that some sequences can adopt two quite different stable structures — and the “wrong” one can be self-propagating.

How prions spread: templated conversion

The key idea is templating. When a PrP^Sc molecule, or a small aggregate of them, meets a normal PrP^C molecule, it acts as a template. The normal protein partly unfolds and is incorporated into the aggregate in the β-sheet shape, becoming PrP^Sc itself.

PrP^C + PrP^Sc → 2 PrP^Sc

Each new PrP^Sc can convert more PrP^C. The aggregates grow into long fibres, which can break into fragments; each fragment is a new “seed” that grows further. This produces an exponential increase — a chain reaction, similar in logic to a nuclear chain reaction or a radical chain reaction (see the chemistry of ageing). It also explains the long incubation period: at first there are very few seeds, and it takes years for the number to grow large enough to damage the brain.

The misfolded aggregates are toxic to nerve cells, which die, leaving the characteristic holes.

Evidence that PrP is essential: mice genetically engineered to lack PrP completely cannot be infected — there’s no normal protein for the prion to convert.

Three ways to get a prion disease

1. Sporadic (about 85 % of human CJD): a PrP molecule misfolds spontaneously, by chance, and starts the chain reaction. Risk increases with age.
2. Inherited (around 10–15 %): mutations in the PrP gene make the protein more likely to misfold. Examples include familial CJD and fatal familial insomnia.
3. Acquired (rare): prions enter from outside — by eating infected tissue (vCJD from BSE-contaminated beef; kuru from ritual funeral practices), or accidentally through medical procedures such as contaminated surgical instruments, corneal grafts, or growth hormone extracted from human pituitary glands (used before synthetic hormone became available in the 1980s).

The UK BSE epidemic is thought to have been amplified by feeding cattle meat-and-bone meal made from rendered animal remains, which recycled infectious material. Changes to rendering processes in the late 1970s and early 1980s may have allowed more prions to survive. A ban on feeding such material to cattle, and removal of high-risk tissues from the food chain, ended the epidemic. Around 180 cases of vCJD were identified in the UK.

Why prions are so hard to destroy

Prions are extraordinarily resistant to methods that kill bacteria and viruses:

• No nucleic acid: ultraviolet and ionising radiation, which destroy DNA and RNA, have little effect.
• Stable β-sheet aggregates: the extensive hydrogen-bonded sheets resist heat and chemicals. Standard autoclaving (121 °C for 15 minutes) isn’t reliably enough.
• Protease resistance: the tightly packed core resists digestion.
• Fixatives such as formaldehyde, which inactivate many microbes, can actually stabilise prions.

Recommended decontamination uses harsh conditions — for example, 1 mol dm⁻³ sodium hydroxide, concentrated sodium hypochlorite (bleach), or longer, hotter autoclave cycles (such as 134 °C for 18 minutes). Hospitals use special procedures, or single-use instruments, for surgery on patients suspected of having prion disease.

Discovery and controversy

In 1982, Stanley Prusiner proposed that scrapie was caused by a “proteinaceous infectious particle”, coining the word prion. Many scientists were sceptical, because it seemed to contradict the idea that infectious agents must carry genetic information. Evidence accumulated over the following years — including experiments with mice lacking PrP, and later, prions made from purified proteins that caused disease in animals. Prusiner received the Nobel Prize in Physiology or Medicine in 1997.

Earlier work was important too: Carleton Gajdusek showed in the 1960s that kuru could be transmitted to chimpanzees, sharing a Nobel Prize in 1976.

Prion-like behaviour in other diseases

The templated spread of misfolded proteins isn’t unique to PrP. In Alzheimer’s disease, amyloid-β peptides and tau protein form β-sheet-rich aggregates; in Parkinson’s disease, α-synuclein forms clumps. Research suggests these misfolded proteins can also seed misfolding in neighbouring cells and spread through the brain in a prion-like way — although, importantly, these diseases are not infectious between people in everyday life.

All of these are examples of amyloid: insoluble fibres built from stacked β-strands running perpendicular to the fibre axis (a “cross-β” structure). Amyloid can form from many unrelated proteins, suggesting it’s a general, low-energy state that polypeptide chains can fall into.

Nature sometimes uses the same trick for good. Some yeast and fungal proteins switch into prion forms that are harmless or even useful, passing traits to daughter cells without any change in DNA.

Common misconceptions

• “Prions are a type of virus.” They contain no genetic material; they’re misfolded host proteins.
• “The prion protein is foreign.” PrP is a normal protein made by our own cells; only its shape is abnormal.
• “Cooking makes contaminated meat safe.” Ordinary cooking doesn’t destroy prions.
• “Alzheimer’s is contagious.” Alzheimer’s proteins show prion-like spread within a brain, but the disease isn’t spread between people by contact.

Key takeaways

• A prion is an infectious misfolded protein with no nucleic acid.
• Normal PrP^C (α-helix-rich, soluble) and prion PrP^Sc (β-sheet-rich, aggregating) have the same sequence but different folds.
• PrP^Sc templates the conversion of PrP^C, giving an exponential chain reaction and a long incubation period.
• Stable hydrogen-bonded β-sheet aggregates make prions resistant to heat, radiation and proteases.
• Prion-like misfolding also occurs in Alzheimer’s and Parkinson’s, via amyloid fibres.

For the basics of how proteins fold into their shapes, see protein structure levels and denaturation.