Prions

• TRANSMISSION ROUTE: Blood transfusion, bone marrow, gastrointestinal, gene mutation, contaminated surgical instruments or biologics, tissue transplants

Definition

The prion is an infectious agent resulting from a misfolding event in the normal PrPc prion protein (a normal cellular membrane protein found in the brain), whereby the alpha-helix structure of PrPc is transformed into a beta-sheet structure, forming PrPsc. This pathogenic (disease-causing) isomer is responsible for causing a group of rare, universally fatal neurodegenerative disorders affecting both humans and animals.

According to the International Code of Virus Classification and Nomenclature, prions are not classified as viruses but are assigned an arbitrary classification, one that seems useful to workers in particular fields. According to the International Committee on Taxonomy of Viruses, prions are classified as subviral agents/satellites.

Natural Habitat and Features

PrPc was discovered by neurologist and biochemist Stanley B. Prusiner, who won the Nobel Prize in Physiology or Medicine in 1997 for his work in this area. He coined the term prion some twenty years after researchers had proposed that an aberrant form of a host protein could be the infectious agent in scrapie, a long-known and fatal disease affecting sheep.

PrPc is anchored to a glycolipid linker molecule and then synthesized in the rough endoplasmic reticulum (the “cellular assembly plant”); it then crosses the Golgi apparatus (distribution organelle) and is dispersed throughout the plasma membrane onto the surface of neurons. Though most PrPc remains concentrated in lipid rafts, some is transported to pit-like areas coated with cell-adhesion cadherins, engulfed by endocytic vesicles, and then recycled. PrPc has 209 amino acids and one disulfide double bond, an alpha-helix structure at its C-terminal half, and is unstructured at its N-terminal half.

The precise functionality of PrPc is not entirely understood, although its location predisposes it to being a membrane receptor, adhesion molecule, or transporter and to having a role in cell-to-cell communication and synaptic function. PrPc appears to be neuroprotective and is protease sensitive (receptive to enzyme breakdown).

As an isomer, PrPsc is chemically identical to its parent protein PrPc but differs in conformation. (In inherited PrPsc, its amino acid sequencing also differs.) The misfolding of PrPc is thought to begin in postsynaptic membranes. On conversion, most of the alpha-helix structure of the host is lost to a large beta-helix that forms and then converts to fibrils (lengths) of beta sheets. This misfolded conformation, the beta-sheet model, constitutes the PrPsc molecule.

The infectious portion of the molecule, designated rPrPsc, is protease-resistant and able to form larger-order aggregates. rPrPsc is thought to propagate by polymerizing and forming amyloid-like fibrils within neurons that deposit as stable aggregates in plasma membranes, inducing conversion of more PrPc. This continuing process causes eventual death to neurons, which are overcome by accumulating aggregates and replaced with large vacuoles (holes).

PrPsc propagation and infectivity pathways are not fully elucidated, leading to much debate over exact mechanisms. The protein-only hypothesis proposed by Prusiner has long been held by scientists as the most plausible theory. This hypothesis maintains that rPrPsc is both toxic and infectious because it is insoluble and forms aggregates that interfere with nerve-cell function. The aggregates break down to release fragments, or seeds, that become conformational templates for other prion proteins to adopt. Protein misfolding cyclic amplification, a process using in vitro purified misfolded protein, supports Prusiner’s theory. Other interesting theories have been postulated, but the complex nature of the prion protein and the mechanisms of its infectivity remain elusive.

Pathogenicity and Clinical Significance

Collectively, prion diseases are a group of transmissible spongiform encephalopathies (TSEs) that affect mammals. They are characterized by the spongelike vacuoles (hence, the term “spongiform”) found in the cortex and cerebellum of the brain postmortem and are the hallmark signs of TSE disease.

Among the best-known TSEs are scrapie, bovine spongiform encephalopathy (BSE, or mad cow disease), and Creutzfeldt-Jacob disease (CJD). Scrapie (the sc in PrPsc stands for “scrapie”) is transmitted by ingestion of infected pasture or transmitted directly from sheep to lamb. Scrapie appears to be genetic and infectious. Chronic wasting disease (CWD) is a TSE that affects deer and elk. No incidence of scrapie or CWD being transmitted to humans has ever been reported.

BSE acquired notoriety in the 1990s when an outbreak occurred in the United Kingdom; up to one thousand cases were reported at its peak, leading to public outcry and political repercussions. First recognized in the 1970s, BSE is believed to have spread from the practice of feeding cattle meat-and-bone meal, which at some point became contaminated with by-products taken from an infected animal.

A chilling consequence of the BSE outbreak was the transmission of the disease to humans. In 1996, a variant of classic CJD (called vCJD) was identified and linked to human consumption of BSE-infected beef products. The link was made because the timing of the outbreak was consistent with known incubation periods for human forms of TSE. European and US authorities were especially concerned because they were unable to make predictions about disease prevalence or incidence.

Prion diseases in humans can be acquired or inherited. There are four types of CJD: sporadic (sCJD), variant (vCJD), familial (fCJD), and iatrogenic. The sporadic or classic form occurs spontaneously for no known reason, while familial is inherited. Variant is thought to be acquired by eating contaminated food, while iatrogenic is transmitted by prion-contaminated materials (such as neurosurgical instruments, tissue implants, and blood). A disease called kuru is also an acquired form of prion disease. Kuru was spread by New Guineans, who practiced cannibalism until the 1950s. Its long incubation period meant that cases were still being reported up to the 1990s.

Inherited forms of TSE include familial CJD, Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI) and are caused by defects in the PrNP gene encoding the prion protein. Twenty such mutations have been identified, involving either amino acid substitutions or repeats of a twenty-four-base-pair segment.

GSS is caused by mutations at codons 102, 117, or 198 and is characterized by progressive cerebellar dysfunction (worsening ataxia, motor problems, and dementia). GSS does not usually become symptomatic until the person is aged forty to fifty years, and it lasts for several years before death.

FFI is caused by a mutation of asparagine for aspartate at codon 178. Patients have intractable insomnia, lack REM (rapid eye movement) sleep, and have sympathetic hyperactivity and other characteristics of CJD.

Drug Susceptibility

There is no cure for TSEs and no viable treatment. However, in 2019 a study reported the development of an anti-prion drug that could significantly delay the progression of TSEs in animals and humans. Researchers have also identified hundreds of potential inhibitors of PrPsc that may someday reduce infectivity or prevent the onset of disease. In the mid-2020s, gene therapies targeting the prion protein gene, targeted protein degradation therapies, and stem cell therapies aimed at repairing damaged neurons caused by misfolded prions emerged as treatments.

Bibliography

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