Prion Disease: A Tale of Folds and Strains

Abstract

Research on prions, the infectious agents of devastating neurological diseases in humans and animals, has been in the forefront of developing the concept of protein aggregation diseases. Prion diseases are distinguished from other neurodegenerative diseases by three peculiarities. First, prion diseases, in addition to being sporadic or genetic like all other neurodegenerative diseases, are infectious diseases. Animal models were developed early on (a long time before the advent of transgenic technology), and this has made possible the discovery of the prion protein as the infectious agent. Second, human prion diseases have true equivalents in animals, such as scrapie, which has been the subject of experimental research for many years. Variant Creutzfeldt-Jakob disease (vCJD) is a zoonosis caused by bovine spongiform encephalopathy (BSE) prions. Third, they show a wide variety of phenotypes in humans and animals, much wider than the variants of any other sporadic or genetic neurodegenerative disease. It has now become firmly established that particular PrP(Sc) isoforms are closely related to specific human prion strains. The variety of human prion diseases, still an enigma in its own right, is a focus of this article. Recently, a series of experiments has shown that the concept of aberrant protein folding and templating, first developed for prions, may apply to a variety of neurodegenerative diseases. In the wake of these discoveries, the term prion has come to be used for Aβ, α-synuclein, tau and possibly others. The self-propagation of alternative conformations seems to be the common denominator of these "prions," which in future, in order to avoid confusion, may have to be specified either as "neurodegenerative prions" or "infectious prions."

Targeting prion propagation using peptide constructs with signal sequence motifs

“…Pinocytosis of prions has also been reported [27,28]. The prion conversion site(s) may vary between different cells [22,[29][30][31][32][33], and most likely depends on factors like prion strain, PrP Sc -subpopulations [34][35][36] as well as uptake routes.…”

Contributions of the Prion Protein Sequence, Strain, and Environment to the Species Barrier

“…Prion proteins, including mammalian PrP and yeast Sup35, not only can fold into alternative prion and non-prion forms but can also adopt multiple distinct amyloid conformations, known as "strains" or "variants" (17,(27)(28)(29)(30)(31)(32)(33). Different strains are associated with distinct disease patterns in mammals and different stringencies of phenotypic effects in fungi (because of this, yeast prion strains can be termed "strong," "intermediate," "weak," etc.).…”

PrPSc-specific antibodies do not induce prion disease or misfolding of PrPCin highly susceptible Tga20 mice

“…4 TSEs of various strains have been observed in humans 5 and an increasing number of domesticated 6 and wild animals. 7 Transmission from cattle to humans through consumption of contaminated meat products in Britain in the late 1980s fueled tight regulations prohibiting the inclusion of ruminant CNS tissues in feed and meat products.…”