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Chronic wasting disease (CWD), a transmissible spongiform encephalopathy that targets cervids, has become a significant threat to both free-ranging and captive populations of Canadian white-tailed deer. In an effort to mitigate its spread, research in the past 20 years has demonstrated that the genetic background of deer may influence the pathogenesis of CWD. Specifically, variants located on the 95-, 96-, 116- and 226-codon of the prion protein gene seem to attenuate disease progression in white-tailed deer. The influence of these alleles on the likelihood of being found CWD-positive on Saskatchewan and Albertan farms was assessed using a Bayesian logistic regression model. To assess the presence of selection for favourable prion protein gene alleles, shifts in variant genotype frequencies were examined over the last seventeen years. Our results show that deer harboring the G96S allele have significantly lowered odds of infection within Canadian herds. Furthermore, the prevalence of this allele has increased significantly in farmed deer over the past seventeen years. Establishing the dynamic genetic background of Canadian deer populations will inform future disease management initiatives.

Chronic wasting disease is a prion disease affecting both free-ranging and farmed cervids in North America and Scandinavia. A range of cervid species have been found to be susceptible, each with variations in the gene for the normal prion protein, PRNP, reportedly influencing both disease susceptibility and progression in the respective hosts. Despite the finding of several different PRNP alleles in white-tailed deer, the majority of past research has focused on two of the more common alleles identified-the 96G and 96S alleles. In the present study, we evaluate both infection status and disease stage in nearly 2100 farmed deer depopulated in the United States and Canada, including 714 CWD-positive deer and correlate our findings with PRNP genotype, including the more rare 95H, 116G, and 226K alleles. We found significant differences in either likelihood of being found infected or disease stage (and in many cases both) at the time of depopulation in all genotypes present, relative to the most common 96GG genotype. Despite high prevalence in many of the herds examined, infection was not found in several of the reported genotypes. These findings suggest that additional research is necessary to more properly define the role that these genotypes may play in managing CWD in both farmed and free-ranging white-tailed deer, with consideration for factors including relative fitness levels, incubation periods, and the kinetics of shedding in animals with these rare genotypes.

To reduce the transmission risk of bovine spongiform encephalopathy prions (PrP BSE ), specified risk materials (SRM) that can harbour PrP BSE are prevented from entering the feed and food chains. As composting is one approach to disposing of SRM, we investigated the inactivation of PrP BSE in lab-scale composters over 28 days and in bin composters over 106–120 days. Lab-scale composting was conducted using 45 kg of feedlot manure with and without chicken feathers. Based on protein misfolding cyclic amplification (PMCA), after 28 days of composting, PrP BSE seeding activity was reduced by 3–4 log 10 with feathers and 3 log 10 without. Bin composters were constructed using ~ 2200 kg feedlot manure and repeated in 2017 and 2018. PMCA results showed that seeding activity of PrP BSE was reduced by 1–2 log 10 in the centre, but only by 1 log 10 in the bottom of bin composters. Subsequent assessment by transgenic (Tgbov XV) mouse bioassay confirmed a similar reduction in PrP BSE infectivity. Enrichment for proteolytic microorganisms through the addition of feathers to compost could enhance PrP BSE degradation. In addition to temperature, other factors including varying concentrations of PrP BSE and the nature of proteolytic microbial populations may be responsible for differential degradation of PrP BSE during composting.

Background Aggregation of the α-Synuclein (α-Syn) protein, amyloid fibril formation and progressive neurodegeneration are the neuropathological hallmarks of Parkinson's Disease (PD). However, a detailed mechanism of α-Syn aggregation/fibrillogenesis and the exact nature of toxic oligomeric species produced during amyloid formation process are still unknown. Results In this study, the rates of α-Syn aggregation were compared for the recombinant wild-type (WT) α-Syn and a structurally relevant chimeric homologous protein containing an inducible Fv dimerizing domain (α-Syn Fv ), capable to form dimers in the presence of a divalent ligand (AP20187). In the presence of AP20187, we report a rapid random coil into β-sheet conformational transformation of α-Syn Fv within 24 h, whereas WT α-Syn showed 24 h delay to achieve β-sheet structure after 48 h. Fluorescence ANS and ThT binding experiments demonstrate an accelerated oligomer/amyloid formation of dimerized α-Syn Fv , compared to the slower oligomerization and amyloidogenesis of WT α-Syn or α-Syn Fv without dimerizer AP20187. Both α-Syn Fv and α-Syn pre-fibrillar aggregates internalized cells and induced neurotoxicity when injected into the hippocampus of wild-type mice. These recombinant toxic aggregates further converted into non-toxic amyloids which were successfully amplified by protein misfolding cyclic amplification method, providing the first evidence for the in vitro propagation of synthetic α-Syn aggregates. Conclusions Together, we show that dimerization is important for α-Syn conformational transition and aggregation. In addition, α-Syn dimerization can accelerate the formation of neurotoxic aggregates and amyloid fibrils which can be amplified in vitro . A detailed characterization of the mechanism of α-Syn aggregation/amyloidogenesis and toxicity is crucial to comprehend Parkinson's disease pathology at the molecular level.

Aggregation of the [alpha]-Synuclein ([alpha]-Syn) protein, amyloid fibril formation and progressive neurodegeneration are the neuropathological hallmarks of Parkinson's Disease (PD). However, a detailed mechanism of [alpha]-Syn aggregation/fibrillogenesis and the exact nature of toxic oligomeric species produced during amyloid formation process are still unknown. In this study, the rates of [alpha]-Syn aggregation were compared for the recombinant wild-type (WT) [alpha]-Syn and a structurally relevant chimeric homologous protein containing an inducible Fv dimerizing domain ([alpha]-Syn.sup.Fv), capable to form dimers in the presence of a divalent ligand (AP20187). In the presence of AP20187, we report a rapid random coil into [beta]-sheet conformational transformation of [alpha]-Syn.sup.Fv within 24 h, whereas WT [alpha]-Syn showed 24 h delay to achieve [beta]-sheet structure after 48 h. Fluorescence ANS and ThT binding experiments demonstrate an accelerated oligomer/amyloid formation of dimerized [alpha]-Syn.sup.Fv, compared to the slower oligomerization and amyloidogenesis of WT [alpha]-Syn or [alpha]-Syn.sup.Fv without dimerizer AP20187. Both [alpha]-Syn.sup.Fv and [alpha]-Syn pre-fibrillar aggregates internalized cells and induced neurotoxicity when injected into the hippocampus of wild-type mice. These recombinant toxic aggregates further converted into non-toxic amyloids which were successfully amplified by protein misfolding cyclic amplification method, providing the first evidence for the in vitro propagation of synthetic [alpha]-Syn aggregates. Together, we show that dimerization is important for [alpha]-Syn conformational transition and aggregation. In addition, [alpha]-Syn dimerization can accelerate the formation of neurotoxic aggregates and amyloid fibrils which can be amplified in vitro. A detailed characterization of the mechanism of [alpha]-Syn aggregation/amyloidogenesis and toxicity is crucial to comprehend Parkinson's disease pathology at the molecular level.