What're prion diseases?

Prions (proteinaceous infectious particle) are infectious self-reproducing protein structures. Though their exact mechanisms of action and reproduction are still unknown, it is now commonly accepted that they are responsible for a number of previously known but little-understood diseases generally classified under transmissible spongiform encephalopathy (TSEs) diseases, including scrapie (a disease of sheep), kuru (found in members of the cannibalistic Foré tribe in Papua New Guinea), and bovine spongiform encephalopathy (mad cow disease). These diseases affect the structure of brain tissue and are all fatal and untreatable.

A typical yeast prion proteins contain a region (domain) with many repeats of the amino acids glutamine (Q) and asparagine (N); these Q/N-rich domains form the core of the prion's structure. Ordinarily, prion domains are flexible and lack a defined structure. When they convert to the prion state, several molecules of a particular protein come together to form a highly structured amyloid fiber. The end of the fiber acts as a template for the addition of free protein molecules, causing the fiber to grow. Small differences in the amino acid sequence of prion-forming regions lead to distinct structural features on the surface of prion fibers. As a result, only free protein molecules that are identical in amino acid sequence to the prion protein can be recruited into the growing fiber. This "specificity" phenomenon may explain why transmission of prion diseases from one species to another (such as from sheep to cows or from cows to humans) is a rare event.

The mammalian prion protein (PrP) does not at all resemble the prion proteins of yeast in its amino acid sequence. Nonetheless, the basic structural features (formation of amyloid fibers and a highly specific barrier to transmission between species) are shared between mammalian and yeast prions. The prion variant responsible for mad cow disease has the remarkable ability to bypass the species barrier to transmission.

The neuropathology of the human prion diseases (CJD, GSS, and kuru) is characterised by 4 features: spongiform change, neuronal loss, astrocytosis and amyloid plaque formation. These features are shared with prion diseases in animals, and the recognition of these similarities prompted the first attempts to transmit a human prion disease (kuru) to a primate in 1966, followed by CJD in 1968 and GSS in 1981.

These neuropathological features have formed the basis of the histological diagnosis of human prion diseases for many years, although it was recognised that these changes are enormously variable both from case to case and within the central nervous system in individual cases.

Early neuropathological reports on human prion diseases suffered from a confusion of nomenclature, in which the significance of the diagnostic feature of spongiform change was occasionally overlooked. The subsequent demonstration that human prion diseases were transmissible reinforced the importance of spongiform change as a diagnostic feature, reflected in the use of the term "spongiform encephalopathy" for this group of disorders.

Prion disease may occur in families because of an inherited susceptibility that makes PrPc molecules more likely to convert to prions. The susceptibility results from a mutation in the gene for PrPc. Many different mutations exist. Each mutation generally causes different prion diseases, which, however, fit into three groups: fatal familial insomnia, familial Creutzfeldt-Jakob disease, and Gerstmann-Sträussler-Scheinker disease. Prion disease may occur when prions are acquired from an external source, such as contaminated beef—as occurs in the so-called variant Creutzfeldt-Jakob disease. Or, prion disease may occur on its own (spontaneously).

More information on prion diseases (Creutzfeldt-Jakob disease, fatal familial insomnia, kuru)