Molecular Mechanisms of Chronic Wasting Disease Prion Propagation

Abstract

Prion disease epidemics, which have been unpredictable recurrences, are of significant concern for animal and human health. Examples include kuru, once the leading cause of death among the Fore people in Papua New Guinea and caused by mortuary feasting; bovine spongiform encephalopathy (BSE) and its subsequent transmission to humans in the form of variant Creutzfeldt-Jakob disease (vCJD); and repeated examples of large-scale prion disease epidemics in animals caused by contaminated vaccines. The etiology of chronic wasting disease (CWD), a relatively new and burgeoning prion epidemic in deer, elk, and moose (members of the cervid family), is more enigmatic. The disease was first described in captive and later in wild mule deer and subsequently in free-ranging as well as captive Rocky Mountain elk, white-tailed deer, and most recently moose. It is therefore the only recognized prion disorder of both wild and captive animals. In addition to its expanding range of hosts, CWD continues to spread to new geographical areas, including recent cases in Norway. The unparalleled efficiency of the contagious transmission of the disease combined with high densities of deer in certain areas of North America complicates strategies for controlling CWD and raises concerns about its potential spread to new species. Because there is a high prevalence of CWD in deer and elk, which are commonly hunted and consumed by humans, the possibility of zoonotic transmission is particularly concerning. Here we review the current status of naturally occurring CWD and describe advances in our understanding of its molecular pathogenesis, as shown by studies of CWD prions in novel in vivo and in vitro systems.

microRNA-146a Signaling in Alzheimer's Disease (AD) and Prion Disease (PrD)

“…(B) Structural features of the miRNA-146a encoding DNA locus at chromosome 5q33.3 and details of the NF-κB-sensitive miRNA146a gene showing three upstream (5 ′ ) canonical regulatory NF-κB binding sites; as might be expected, miRNA-146a transcription is highly sensitive to induction by NF-κB (2,3,14,15,20,21); (C) pre-miRNA-146a transcribed from the miRNA-146a locus has the intrinsic potential to form an extremely stable 35-base-pair stem, 60-nucleotide loop sncRNA structure (stem-loop E A = −49.5 kcal/mol) with miRNA-146a encoded in the distal loop; several other secondary structures of alternate miRNA-146a-stem-loop containing configurations are possible and the 5 ′ and 3 ′ ends of pre-miRNA-146a may be significantly extended; in all other high-stability precursor miRNA-146a models, the stem-loop structure containing the mature miRNA-146a sequence is consistently located in the very distal end of the predicted loop [DNA sequence shown; upper case; highlighted in yellow and delineated by arrows on the left side of (C)]; RNA-polymerase II-based transcription and processing by Dicer (RNase III) of the miRNA-146a-5p precursor (pre-miRNA-146a-5p) generated by this unique stem-loop structure yields a mature miRNA-146a-5p [miRNA-146a-5p sequence over-lined with a yellow bar in sequence of their proximal promoter regulatory regions (9-12) (Figure 1). One of these miRNAs is miRNA-146a, normally only moderately abundant in the human brain neocortex and hippocampus, but inducible to many times its basal level by pathogenic agents associated with stress, pro-inflammatory glycolipids (such as LPS), local levels of reactive oxygen species (ROS), and the abundance of Aβ42 peptides and prion amyloids whose accumulation are characteristic, respectively, of the human disorders Alzheimer's disease (AD) and prion disease (PrD) (11,12,14,(24)(25)(26)(27)(28)(29)(30)(31)(32). For example, in one study, Genechip-and microfluidic fluorescent array-based and/or LED-Northern dot blot miRNA analysis that interrogates the entire 2,650 miRNAs yet characterized in human brain tissues revealed a selective upregulation of miRNA-146a in 36/36 short post-mortem interval (PMI) human superior temporal lobe neocortical tissue specimens analyzed, compared to 30-age-, gender-, and PMImatched controls (all PMIs < 3.1 h) (10-12, 14, 24, 25).…”

Chronic wasting disease associated with prion protein gene (PRNP) variation in Norwegian wild reindeer (Rangifer tarandus)

“…Interestingly, the structure of the β2-α2 loop, encompassing residues 165-175 (codons 168-178 in reindeer PRNP), has been shown to be important for interspecies transmission of prion disease in mice models [35] and the rigidity of the β2-α2 loop, common to cervids [36], at least partly explains the efficient transmission of CWD between cervid species [37]. Recent data suggest that long-range stabilizing interactions between the β2-α2 loop and α3 affect prion propagation [38,39]. For instance, 3D simulations have shown that Ser225Phe, results in a rearrangement allowing a stabilizing hydrogen bond to be established between the β2-α2 loop and α3 that could explain the reduced susceptibility associated with this substitution [30].…”

Association of chronic wasting disease susceptibility with prion protein variation in white-tailed deer (Odocoileus virginianus)

“…CWD was first identified in mule deer (O. hemionus hemionus) and black-tailed deer (O. h.columbianus) in captivity in Colorado and Wyoming in 1967 [5][6][7]. Since then, CWD has spread to additional species and affects free-ranging Cervidae in 24 US states, two Canadian provinces, Norway, Finland, and Sweden [8].…”

“…A scrapie eradication programme based on genetic susceptibility has been implemented in the United States [34]. While such a programme would be impractical for free-ranging animals, a better understanding of disease susceptibility would inform potential management intervention [6,7,35,36].…”