A Hypothesis for Prion Disease Jorma Jyrkkanen Researcher 2/4/24

Prion Diseases CWD, CJD, BSE, Crappie, KURU Busted. A Hypothesis. 30 Sept 2018 Jorma Jyrkkanen Sep. 30th, 2018 at 11:00 AM Jormawankenobe Plays Electric 12 String Original: BSE, Crappie, CWD, CJD Busted?? 30 Sept 2018 Jorma Jyrkkanen, Researcher

Glutamine linked to toxic beta-pleated alpha helices in the conformation of prions. So where and why does glutamine suddenly start this process. A single prion polymer may be the trigger from what I can tell. "Our computational and experimental analyses indicate that Qs (glutamine), specifically, increase the propensity for toxic interactions by disordered proteins, which, in turn, may contribute to the pathology of Q-rich proteins in disease." My suspicion turns now to dietary sources and here they are: High glutamine Foods: While animal proteins are highly rich in glutamine, there are numerous vegetables as well that would do the trick. Meat. Meat contains very high amount of protein. Seafood. Fish is a great source of glutamine, Milk, Nuts, eggs, cabbage, Protein drinks, Beans, Protein Drinks. But, how does the glutamine get past the blood brain barrier? Doesn't have t not that it cannot find a way by say a mutant transporter. Glutamine is synthesized by brain Glial cells and is transformed into glutamate by mitochondrial enzyme glutaminase. My suspicion now transfers to brain mitochondrial health and glutaminase production and Glial cell glutamine production and damaged blood brain barriers to dietary glutamine permeability. Here I get an AHA moment. I recall a mitochondrial antibiotic study by Sameer Calghatgi. Antibiotics can produce lipid peroxides which can rupture mitochondria and ROS which can lead to mutations in P53 genes. This is a clue the stressor that might be linked to aberrant glutamine production by Glial cells (might not be getting the enzyme for conversion to glutamate ) so that antibiotics or related substances trigger pathological prion folding by excess glutamine buildup in the brain. microRNAs might be connected to this story by virtue of being a bad boy in the protein folding story. EMBO J. 2014 Jul 1; 33(13): 1428–1437 Emde and Hornstein Abstract microRNAs (miRNAs) are a family of small, non-coding RNAs, which provides broad silencing activity of mRNA targets in a sequence-dependent fashion. This review explores the hypothesis that the miRNA machinery is intimately linked with the cellular stress pathway and apparatus. Stress signaling potentially alters the function of the miRNA-bioprocessing core components and decompensates regulation. In addition, dysregulation of miRNA activity renders the cell more prone to stress and emerges as a new pathway for age-related insults and diseases, such as neurodegeneration.Keywords: cellular stress, dicer, disease, micrornas, stress granules Worth testing. The views and opinions expressed in this paper are solely those of the author and do not necessarily reflect those of CAPI. The Canadian Agri-Food Policy Institute 960 Carling Avenue, CEF Building 60 Ottawa, ON K1A 0C6 Telephone: 613-759-1027 www.capi-icpa.ca Canadian Agri-Food Policy Institute Chronic Wasting Disease and the Canadian Agriculture and Agri-food Sectors: Current Knowledge, Risks and Policy Options i Liability Statement This report was developed based on current information and accepted disciplinary methodology. Users of the data and information contained herein are solely responsible for its use. The authors are not liable for any loss or damage arising from use of the information contained in this report. Funding and Disclaimer The report was prepared as information for the Canadian Agri-Food Policy Institute. However, the views and opinions expressed in this report are not necessarily those of the Canadian Agri-Food Policy Institute. Acknowledgements The authors would like to thank CAPI for the opportunity to develop this report and for their feedback and commentary. The authors would also like to thank the funding agencies who supported research that provided information reported in this manuscript. These agencies include the Alberta Prion Research Institute, Genome Alberta, Genome Canada, PrionNet and SSHRC. The authors would also like to thank collaborators at the University of Alberta, University of Calgary and government agencies for their support, collaboration and commentary on the analysis of the social science aspects of CWD, including, Brenda Parlee, Lusi Xie, Anne Hubbs, Evie Merrill, Hermann Schaetzl, Matt Besko and Margo Pybus. The authors would like to thank Dr. Penny Greenwood of the CFIA for her valuable comments on an earlier draft of this report. We also wish to thank the participants in the CAPI workshops and the anonymous reviewers for comments. Remaining errors or omissions are the responsibility of the authors. Suggested Citation Adamowicz, W., Goddard, E, Luckert, M and J. Pattison-Williams, with A. Otero Garcia, D. McKenzie, J. Aiken, G. Durocher, Merlin Uwalaka, A. Klotz and J. Flesch. 2021. Chronic Wasting Disease and the Canadian Agriculture and Agri-food Sectors: Current Knowledge, Risks and Policy Options. A Report Prepared for the Canadian Agri-Food Policy Institute. Canadian Agri-Food Policy Institute Chronic Wasting Disease and the Canadian Agriculture and Agri-food Sectors: Current Knowledge, Risks and Policy Options ii EXECUTIVE SUMMARY Chronic Wasting Disease (CWD) is a prion disease that affects cervid (deer) species and has been found in both wild and farmed populations in the U.S., Canada and abroad. In this report policy options that may be relevant to reducing the impact of CWD on the Canadian agri-food and agriculture sector are described. Given the nature of the disease, policy options are relevant to either the farmed or wild sector or both, as appropriate. The policy options are situated in the context of the current state of knowledge, stakeholder and rightsholder risk perceptions and policy preferences. The disease was initially observed in research facilities of Colorado and Wyoming in the late 1960s. In Canada, the first CWD cases were identified, retrospectively, in mule deer at the Toronto Zoo, from post- mortems on animal samples from deaths over the period 1973 to 1981 (7 positive animals found from deaths occurring over the period 1975 to 1979) (Dubé et al, 2006). The first farmed cervid was found with the disease in 1996 in a Saskatchewan elk farm (in captive elk that were imported from South Dakota (Williams and Miller, 2002)). In the following years, CWD was detected in farmed white-tailed deer and elk in Alberta and in wild cervid populations from Saskatchewan and Alberta (Kahn et al., 2004). CWD was found in a red deer farm in Quebec in 2018. CWD prevalence in North America has greatly increased in the last decade. Prion infectivity persists in the environment—animal carcasses, predator faeces, soil and plants—for more than 10 years, serving as a long-term source of infection (Georgsson et al., 2006). To date, no natural transmission of CWD to species outside the Cervidae family has been documented in wild or domestic animal populations but research is on-going. The transmission of prions from one species to another is limited by a transmission barrier. The strength of this barrier depends on multiple factors including the primary sequence of the PrPC of the new host and the PrPCWD from the inoculum and the transmitted prion strain (e.g., Hill et al., 2000). Experimental data, however, has shown that the transmission of CWD to other species, such as cats, pig, sheep and rodents, is possible. Of special concern is the possible transmission of CWD to non-cervid species used in the human food supply chain, especially cattle and other livestock, due to the potential emergence of prions with zoonotic capacity (as with bovine spongiform encephalopathy (BSE)). The interaction of cattle and cervids is common in CWD-affected areas of North America. CWD agents from different species (white-tailed deer, mule deer and elk) are transmissible to cattle after intracerebral inoculation (Hamir et al., 2005; Hamir et al., 2007b; Hamir et al., 2011b; Greenlee et al., 2012), and the characteristics of the disease are very different from BSE (Hamir et al., 2011b). In experimental treatments, no oral transmission of CWD to cattle has occurred, and no CWD prions were detected in cattle that were exposed to CWD- contaminated paddocks for 10 years (Williams et al., 2018). Thus, the risk of CWD transmission to cattle from normal interaction with cervids is currently believed to be very low. There is no evidence of transmission to humans, yet there are concerns about the zoonotic potential of CWD. Nonetheless, questions remain regarding CWD transmission to other wild and domestic animals, into the human food supply (in the case of untested animals and antler velvet) or to humans themselves. Further research into Canadian Agri-Food Policy Institute Chronic Wasting Disease and the Canadian Agriculture and Agri-food Sectors: Current Knowledge, Risks and Policy Options iii these issues is needed. Furthermore, active disease management practices are warranted to minimize the risk of CWD transmission. The perspectives of rightsholders and stakeholders impacted by CWD are important for future policies. Using primary survey data, supplemented by secondary data sources, we present the level of knowledge, attitudes and management preferences for CWD. Although the methods to elicit these perspectives has some variation due to the unique characteristics of each group, several trends were observed: Canadian Public: • Over time, the number of people who have ever eaten venison has increased. Eating frequency does not appear to be increasing across the population over time • Awareness and knowledge of CWD has dramatically declined across time. • The public is significantly interested in mandatory CWD animal testing before meat is marketed and continues to be interested in supporting tax increases to pay for management or surveillance. This implies that healthy cervid populations are important to the Canadian public. Indigenous Rightsholders • Ungulates (noting particularly caribou to whom transmission is possible) are a major component of food security for Indigenous peoples, but also contribute to significant cultural values including sharing networks. • Concerns about cultural tipping points, arising from environmental conditions, costs, and time constraints of local people, have been expressed by First Nations. However, safety of ungulate meat is an important concern, given the dietary role of cervids. • The Alberta Assembly of Tribal Chiefs, representing First Nations in Treaty 6, 7 and 8, passed a resolution in June 2019 supporting collaborative research on CWD surveillance. • There are questions about how the continued spread of CWD, as well as management efforts (e.g., health advisories), has the potential to contribute to increased food insecurity among Indigenous communities, whose traditional economies are also compromised by other stresses, such as habitat degradation and climate change. • A greater role of communities in disease surveillance (e.g., monitoring) and in decisions of wildlife management may contribute to both social and ecological resilience. Communication and management programs must be centered in the Indigenous communities with recognition of the importance of the cultural significance and context of wildlife. Cervid Producers • Cervid farming in Canada was a relatively new industry when CWD was discovered in the farmed sector in Canada. Canadian Agri-Food Policy Institute Chronic Wasting Disease and the Canadian Agriculture and Agri-food Sectors: Current Knowledge, Risks and Policy Options iv • CWD caused a serious negative economic shock to the industry, which has been declining in total farms and total animals since CWD was found. • Cervid farmers are very aware of and knowledgeable about CWD due to the significant economic impact on the industry • The herd certification program (originally VHCP, now HCP), initiated in 2002 and revamped in 2018, is aimed at preventing CWD exposure, certifying safe cervid production for consumption or trade purposes, and is a prerequisite for the federal government undertaking destruction of a confirmed infected herd and compensating owners should CWD be discovered. Some provinces have complementary programs. • Mandatory testing for all farmed cervids slaughtered (or other deaths) in Alberta, Saskatchewan, Manitoba, Quebec (rather than sampling as was done prior to 2018) and the Yukon makes testing rates for CWD among farmed cervids higher than in wild cervids; positive cases recently are lower in absolute numbers relative to wild cervids. Alberta Hunters • An extensive CWD monitoring and surveillance program, and hunter surveys in the province, have shown relatively constant hunter awareness and perceptions of CWD over time. • License sales are not declining over time, indicating that hunters are not reducing their effort, even with moderately high levels of CWD present. Hunters are concerned about CWD impacts on wildlife herd health, and do not think eradication is likely. • US research indicates reduced hunting effort occurs when CWD reaches high (>30%) prevalence levels. While this is not evident yet in Canada, increasing numbers of hunters are checking prevalence levels prior to draw submission, indicating a shift could occur if prevalence increases dramatically. • Management options such as hunting season expansion can provide a high benefit-low cost approach to CWD management rather than financially and socially costly herd reduction approaches. • The removal of the replacement tag program in Alberta in 2019 (for harvested deer that test positive) was not popular among some hunters although recent data suggests that the majority of hunters are not opposed to this change in program. (Source: Adamowicz et al. 2019, 2020). Professional Outfitters • Survey results show that outfitters had the highest awareness of the disease in wild cervids when compared with other stakeholder groups, yet did not support CWD management options that increase hunting of animals • Their views about acceptable management strategies differ considerably from hunter views and from views of the public • Even given the severity of CWD spread in parts of the country, CWD is not seen to be the most significant risk to outfitter livelihood associated with cervid populations. Canadian Agri-Food Policy Institute Chronic Wasting Disease and the Canadian Agriculture and Agri-food Sectors: Current Knowledge, Risks and Policy Options v Cow Calf Cattle Operations • Wild ungulates are a concern in terms of disease transmission (CWD and other diseases) and feed consumption. • Producers generally like cervids and do not want to see them eradicated from their properties and worry about costs of reducing contact between cattle and cervids. • Preliminary results indicate limited concern over possible trade barriers impacting the beef industry due to CWD. There are numerous policy response areas related to CWD that are being considered. The policy space is complicated by the potential for the disease to cross both wildlife and domesticated animals, as well as provincial and national borders. Commensurately, there are a complex set of agencies associated with parts of the policy environment. No one agency has authority over all of the recommended or identified policy areas considered below. Associated industries are also involved in policy making processes and could implement codes of conduct to address CWD. However, clarifying which and how policy options might be implemented (including identifying any coordinating agency responsibilities) is still to be determined. The disease is considered to have differing degrees of urgency among constituencies and development of policies based on risk assessments must be careful not to be too reactive as the trade-offs can be difficult to assess ex ante. Despite these difficulties, we identify and discuss 10 policy options. The focus is primarily on policies that directly (cervid farm) and indirectly (through reducing spread and prevalence in the wild) affect the Canadian agri-food and agriculture sectors. The ten options chosen are those for which there are frequent recommendations or for which the outcomes seem clearer given previous policies applied across a range of North American jurisdictions and based on research findings to date. In most cases, due to limited publicly available data on the costs of programs which have been implemented by federal or provincial agencies, it is not possible to develop consistent measures of costs or benefits of the suggested policies to specific groups. Decisions around policy adoption in this area cannot purely be made on the basis of market costs and benefits as the disease being managed has the capacity to inflict high non-market costs. Significant research is necessary to properly assess public and private market and non-market values associated with the outcomes of policy choices. Furthermore, additional detail on a range of items including enforcement efficacy and cost, communication approaches and other elements will be required for a complete analysis. Nevertheless, we present an overview of ten policy areas which can be described as having the most potential for reducing the impact of CWD on the Canadian agri-food and agriculture sectors. Later in the document we identify a broader range of policy measures to be considered that include investing in research and other measures to address CWD concerns. The References: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3132398/ Published online 2014 May 27. doi: 10.15252/embj.201488142 PMCID: PMC4194087 PMID: 24867813 miRNAs at the interface of cellular stress and disease Anna Emde and Eran Hornstein* CWD and the Agrifood Industry and Hunting Tags: antibiotics, folding, glial cells, glutaminase, glutamine, mitochondria, prion disease