Prions are unique infectious agents, composed solely of protein without genetic material like DNA or RNA. They cause rare, fatal neurodegenerative conditions called transmissible spongiform encephalopathies (TSEs) in humans and animals. Prions lead to abnormal protein folding in the brain, causing damage and a sponge-like appearance in affected tissue. Understanding prion formation is important, as these progressive diseases currently lack effective treatments.
The Normal Prion Protein
The cellular prion protein, PrP^C, is the normal, healthy form found throughout the body, with high concentrations in the brain. This glycoprotein is located primarily on the outer surface of cell membranes.
Structurally, PrP^C is characterized by a high proportion of alpha-helices. It also contains a short antiparallel beta-sheet and a single disulfide bond connecting two of its alpha-helices. The exact physiological functions of PrP^C are still being investigated, but it is involved in various cellular processes, including protecting cells from oxidative stress, regulating cell signaling, and maintaining synapses.
The Core Misfolding Event
The fundamental step in prion formation involves a dramatic change in the protein’s three-dimensional shape. This transforms the normal cellular prion protein (PrP^C) into its abnormal, disease-causing counterpart, PrP^Sc. While PrP^C is rich in alpha-helical structures, the misfolding converts these into beta-sheets, a key characteristic of PrP^Sc.
This change makes PrP^Sc highly stable, resistant to degradation, and insoluble. Unlike soluble PrP^C, misfolded PrP^Sc tends to aggregate, forming insoluble clumps. This conformational shift is central to prion diseases, enabling the protein to propagate its misfolded state. The altered structure of PrP^Sc means it can no longer perform the functions of PrP^C.
Initiating Prion Formation
The initial misfolding of PrP^C into PrP^Sc can be triggered in several ways. The most common human prion disease, sporadic Creutzfeldt-Jakob disease (CJD), occurs when misfolding happens spontaneously for unknown reasons. This spontaneous change affects approximately one in every million people annually.
Inherited forms of prion disease arise from specific mutations in the PRNP gene, which provides instructions for making the prion protein. These genetic alterations make PrP^C inherently more susceptible to misfolding into the PrP^Sc conformation, leading to various inherited prion diseases like familial CJD.
Prion formation can also be acquired through exposure to an external source of misfolded prions. This occurs when an individual consumes contaminated products, such as meat from animals with bovine spongiform encephalopathy (BSE), or through medical procedures involving contaminated tissues or instruments. While rare, such exposure can introduce PrP^Sc, which then initiates the misfolding process within the host.
The Prion Replication Process
Once an initial misfolded prion (PrP^Sc) is present, it acts as a template, coercing healthy PrP^C molecules to change into the abnormal PrP^Sc form. This process is often described as a “chain reaction” or autocatalytic conversion, where PrP^Sc accelerates the misfolding of more PrP^C. It is a self-propagating mechanism that does not require genetic material.
As more PrP^C molecules convert to PrP^Sc, these misfolded proteins aggregate, forming insoluble clumps known as amyloid fibrils. These aggregates accumulate in brain tissue, leading to cellular damage and the characteristic sponge-like vacuolation seen in prion diseases. The accumulation of these resistant protein aggregates ultimately disrupts neuronal function and causes cell death.