Canadian Researchers Receive $2.9 Million to Protect Against Prion Disease Outbreaks, Develop Novel Therapies to Treat Alzheimer’s, Parkinson’s and ALS
Scientists find increasing connection between development of prion disease and common human neurodegenerative disorders
July 13, 2011 (Vancouver, BC) – Collaborative research groups at nine different universities, involving 55 different investigators across Canada, are poised to make significant advances in the understanding of prion and prion-like diseases in humans and animals. These include the development of an oral vaccine to help stop the spread of chronic wasting disease (CWD) in wild deer and elk populations and novel approaches to treat human neurodegenerative disorders like ALS (Lou Gehrig's disease), Alzheimer’s and Parkinson’s diseases, thanks to $2.9 million in funding announced by PrioNet Canada.
The goal of the funding which supports 11 projects is two-fold, explains Dr. Neil Cashman, Scientific Director of PrioNet Canada, one of Canada’s Network of Centres of Excellence. “By working with our partners, we aim to continue to protect Canada against classical prion diseases like chronic wasting disease and mad cow disease (bovine spongiform encephalopathy or BSE), and we’re also providing benefit to Canadians through the development of innovative therapeutics to treat neurodegenerative diseases like Alzheimer’s, Parkinson’s and ALS.”
The researchers will use the funds to better understand the biology of prion disease, to develop strategies to manage prion disease outbreaks and minimize the impacts, and to apply learnings of prion diseases to the treatment of human neurodegenerative disorders.
Prion diseases are fatal, infectious and transmissible diseases of humans and animals associated with a ‘sponge-like’ degeneration of brain tissue. In animals, the most common prion diseases include BSE, scrapie in sheep and goats, and CWD in deer and elk. In 2003, Canada’s beef and related industries were faced with worldwide closing of trade after a domestic case of BSE was found in Alberta. Canada’s economic loss stemming from this event is estimated at more than $6 billion. Some examples of prion diseases in humans include fatal and sporadic familial insomnia, Creutzfeldt-Jakob disease (CJD) and its many varieties, and Kuru. Some examples of the ground-breaking work supported by PrioNet’s recent funding include:
• Immunotherapies to treat ALS: Five PrioNet researchers at the University of British Columbia, University of Alberta and University of Toronto are focusing on a newly-recognized molecular mechanism of ALS, a misfolded protein called SOD-1. By identifying the parts of the protein that are exposed when it is misfolded in disease, researchers are able to design immunotherapies that can target those areas, interrupting the slow progression of paralysis and eventual death characterized by the disorder. Two animal models have already demonstrated responsiveness to the new immunotherapies and work is now underway to develop a therapy for humans. “We are hoping these discoveries could prove to be a magic bullet for ALS,” said Dr. Cashman, who serves as principal investigator for the multi-disciplinary research team.
• Oral vaccine to control chronic wasting disease in the wild: Prion diseases like chronic wasting disease are continuing to spread throughout the Canadian prairie’s wild deer and elk populations and ten PrioNet researchers in Saskatoon and British Columbia are working on an oral vaccine to stop the spread. “The danger is that prion diseases are evolving and new strains are emerging,” noted Dr. Scott Napper, a Research Scientist with the Vaccine and Infectious Disease Organization in Saskatoon and principal investigator on the project. Dr. Napper’s group is focusing on an oral vaccine that can withstand extreme temperatures and will effectively attract elk and deer in the wild. Similar oral vaccines are already used to control rabies in Eastern Canada, where food packets containing the vaccine are widely distributed for consumption by fox and raccoon populations.
• Framework to minimize the impact of chronic wasting disease: Principal investigator Dr. Ellen Goddard from the University of Alberta along with nine co-investigators are working to identify the risk factors associated with chronic wasting disease in wild deer and elk populations, how they can be managed and what public policy recommendations should be put in place to try and mitigate the effects. The primary goal is to monitor the many unknowns that remain about the impact of CWD in the wild, such as the potential risk to hunters who consume infected animals and the potential interface between wild and domestic animals. “The risk management framework around BSE showed that even though countries were aware of the disease in their cattle, they completely underestimated the economic impact and the public response,” notes Dr. Goddard. “We’re doing the work ahead of the game while CWD is still manageable and while effective policies can be put into place to control it, to help anticipate and prevent the impacts.”
• Understanding ‘good versus bad’ prions in order to develop drugs: The first step to designing drugs to treat prion and prion-like diseases is to understand how prion proteins change shape when they become “misfolded” in disease. Dr. Christoph Borchers, a Professor in the Department of Biochemistry and Microbiology and Director of the University of Victoria-Genome BC Proteomics Centre is collaborating with researchers from the University of Alberta and University of Western Ontario to characterize the changes that occur to the three-dimensional structure of prion fibrils (small, nerve-like fibres) as well as the molecular mechanisms that lead to those changes. Using a combination of protein chemistry and mass spectrometry, they are working to explain what occurs when a ‘good’ prion protein changes to a ‘bad’ one during disease development. The information is crucial to designing drugs that can interfere with those changes, effectively curbing the spread of prion and prion-like diseases.
About PrioNet Canada (www.prionetcanada.ca) One of Canada’s Networks of Centres of Excellence, PrioNet Canada is a pan-Canadian research network that is developing strategies to help solve the food, health safety, and socioeconomic problems associated with prion diseases. The network brings together academia, industry, and public sector partners through its multidisciplinary research projects, training programs, events, and commercialization activities to help derive maximum socioeconomic benefits for Canadians. PrioNet is hosted by the University of British Columbia and the Vancouver Coastal Health Research Institute in Vancouver.
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Media information or to set up interviews: Gail Bergman or Christina Vetro Gail Bergman PR Tel: (905) 886-1340 or (905) 886-3345 E-mail: firstname.lastname@example.org
Last Updated: 7/13/2011 11:27:59 AM
All Other Emerging and Zoonotic Infectious Diseases CDC's FY 2012 request of $52,658,000 for all other emerging and zoonotic infectious disease activities is a decrease of $13,607,000 below the FY 2010 level,
which includes the elimination of Prion activities ($5,473,000),
a reduction for other cross-cutting infectious disease activities, and administrative savings. These funds support a range of critical emerging and zoonotic infectious disease programs such Lyme Disease, Chronic Fatigue Syndrome, and Special Pathogens, as well as other activities described below.
" the FY 2010 level, which includes the elimination of Prion activities ($5,473,000), "
USDA MAD COW PROBLEMS SOLVED $$$
Saturday, June 25, 2011
Transmissibility of BSE-L and Cattle-Adapted TME Prion Strain to Cynomolgus Macaque
"BSE-L in North America may have existed for decades"
Sunday, June 26, 2011
Risk Analysis of Low-Dose Prion Exposures in Cynomolgus Macaque
Thursday, June 23, 2011
Experimental H-type bovine spongiform encephalopathy characterized by plaques and glial- and stellate-type prion protein deposits
Wednesday, June 15, 2011
Galveston, Texas - Isle port moves through thousands of heifers headed to Russia, none from Texas, Alabama, or Washington, due to BSE risk factor
Saturday, July 23, 2011
CATTLE HEADS WITH TONSILS, BEEF TONGUES, SPINAL CORD, SPECIFIED RISK MATERIALS (SRM's) AND PRIONS, AKA MAD COW DISEASE
Thursday, June 2, 2011
USDA scrapie report for April 2011 NEW ATYPICAL NOR-98 SCRAPIE CASES Pennsylvania AND California
Monday, June 20, 2011 2011
Annual Conference of the National Institute for Animal Agriculture ATYPICAL NOR-98 LIKE SCRAPIE UPDATE USA
Monday, June 27, 2011
Comparison of Sheep Nor98 with Human Variably Protease-Sensitive Prionopathy and Gerstmann-Sträussler-Scheinker Disease
Monday, November 30, 2009
USDA AND OIE COLLABORATE TO EXCLUDE ATYPICAL SCRAPIE NOR-98 ANIMAL HEALTH CODE
I strenuously urge the USDA and the OIE et al to revoke the exemption of the legal global trading of atypical Nor-98 scrapie TSE. ...TSS
Friday, February 11, 2011
Atypical/Nor98 Scrapie Infectivity in Sheep Peripheral Tissues
Thursday, November 18, 2010
Increased susceptibility of human-PrP transgenic mice to bovine spongiform encephalopathy following passage in sheep
Sunday, October 3, 2010
Scrapie, Nor-98 atypical Scrapie, and BSE in sheep and goats North America, who's looking ?
Wednesday, July 06, 2011
Swine Are Susceptible to Chronic Wasting Disease by Intracerebral Inoculation
(see tonnage of mad cow feed in commerce USA...tss)
Monday, June 27, 2011
Zoonotic Potential of CWD: Experimental Transmissions to Non-Human Primates
Please see the following warning from CDC about prion TSE consumption in North America ;
Thursday, May 26, 2011
Travel History, Hunting, and Venison Consumption Related to Prion Disease Exposure, 2006-2007 FoodNet Population Survey
Journal of the American Dietetic Association Volume 111, Issue 6 , Pages 858-863, June 2011.
Tuesday, July 19, 2011
Neuroanatomical Distribution of Disease-Associated Prion Protein in Cases of Bovine Spongiform Encephalopathy Detected by Fallen Stock Surveillance in Japan
Saturday, March 5, 2011
MAD COW ATYPICAL CJD PRION TSE CASES WITH CLASSIFICATIONS PENDING ON THE RISE IN NORTH AMERICA
Oral.01: Changing Spectrum of Prions
University of California San Francisco, Institute for Neurodegenerative Diseases; San Francisco, CA USA
Prions are self-propagating forms of proteins found in eukaryotes. Prions are created from benign, cellular precursor proteins by a posttranslational modification that is self-perpetuating. Often the prion form of the protein is aggregated and assembles into amyloid polymers. Prions can be inherited both genetically and epigenetically. In neurodegenerative diseases, the formation of prions is heritable through mutations in the gene encoding the cellular form of the prion protein. In fungi, the prion state is epigenetically transferred from mother to daughter cells.
Historically, prions were confined to a small group of infectious CNS illnesses including Creutzfeldt-Jakob disease (CJD) and kuru of humans, scrapie of sheep, bovine spongiform encephalopathy, and chronic wasting disease of deer and elk. CJD can present as an infectious, inherited or sporadic illness. In all three manifestations of the disease, the cellular prion protein (PrPC) refolds into the disease-causing isoform (PrPSc). A truncated form of PrPSc readily polymerizes into amyloid fibrils and forms PrP amyloid plaques. Prion strains composed of different conformers of PrPScSc have been identified. Subsequently, prions were recognized in fungi and studied extensively using yeast. Recently, self-propagation of altered proteins that cause several neurodegenerative diseases, including Alzheimer disease and the tauopathies, has been demonstrated using cultured cell and transgenic mouse models. Increasing evidence argues that the Ab peptide acts as a prion in that it stimulates the de-novo formation of more Ab peptide. Similarly, the aggregates of Tau provoke the assembly of more aggregated Tau. In addition, fetal grafts of substantia nigra in patients with advanced Parkinson’s disease exhibit Lewy bodies, arguing that a-synuclein may act as a prion. Misfolded a-synuclein is thought to transit from the patient’s neurons to those in the graft, where it stimulates the de-novo formation of aberrantly folded a-synuclein into Lewy bodies.
The spread of misprocessed proteins in the human CNS is also consistent with the Ab peptide, hyperphosphorylated Tau and misfolded a-synuclein being prions. In Alzheimer disease, Ab plaques and neurofibrillary tangles (NFTs) begin in the entorhinal cortex and spread throughout the brain. In a delayed form of traumatic brain injury, NFTs appear to spread outward from points of impact. Misfolded a-synuclein has been found along the vagus nerve where it appears to migrate retrograde into the CNS.
Increasing evidence that posttranslationally altered proteins are responsible for the major neurodegenerative diseases widens the spectrum of prion disorders. Moreover, prions with glutamine/asparagine-rich regions like those in yeast and aplysia have given unique insights into the normal function of alternatively processed, self-propagating proteins.
Oral.33: Transmission of Alzheimer Disease and Type 2 Diabetes by a Prion Mechanism
Claudio Soto,1,† Natalia Salvadores-Bersezio,1 Ines Moreno-Gonzalez,1 Claudia Duran-Aniotz,1, 2 Akihiko Urayama,1 Lisbell Estrada,3 Diego Morales-Scheihing1, 2 and Rodrigo Morales1
1Protein Misfolding Disorders Lab, Mitchell Center for Alzheimer Disease and Related Brain Disorders, Department of Neurology; University of Texas Medical School at Houston; Houston, TX USA; 2Facultad de Medicina, Universidad de Los Andes; Santiago, Chile; 3 Universidad Catolica de Chile; Santiago, Chile†Presenting author; Email: Claudio.Soto@uth.tmc.edu
Alzheimer disease (AD) and type 2 diabetes (T2D) are the most prevalent diseases of the group of protein misfolding disorders (PMDs). A hallmark event in the pathology of AD and T2D involves the misfolding, aggregation and accumulation of Ab and IAPP, respectively. Considering that the molecular mechanisms responsible for protein misfolding and aggregation in PMDs are strikingly similar to the process of prion replication we hypothesize that all these diseases have the inherent capability of being transmissible. Recent exciting studies from various groups have provided strong proof-of-concept for the transmission of the pathological hallmarks of various PMDs in an experimental setting. In this presentation we will provide further evidence for the induction of AD and T2D features in animal models of these diseases upon intra-cerebral and intra-peritoneal inoculation of tissue homogenates containing Ab and IAPP aggregates, respectively. One of the key questions regarding prion-like transmissibility of other PMDs is whether this phenomenon can occur by practically relevant routes of exposure. To study this issue, we assessed whether these diseases can be induced by transfusion of blood from animals exhibiting large quantities of cerebral or pancreatic aggregates. Blood transfusion was chosen because is a medically relevant route of exposure to potentially infectious material and because the data in animals and even in humans is solid to support blood transfusion as a route of prion infection in TSEs. Our results show that infusion of blood from old AD or T2D transgenic mice into young animals significantly accelerates the onset of pathological and clinical abnormalities associated to these diseases. Our results indicate that the two most prevalent PMDs can be initiated by exposure to misfolded protein aggregates, which replicate in the body in a similar manner as infectious prions. These findings may open a new avenue to understand the origin of AD and T2D and may provide new strategies for disease intervention and prevention.
PPPM.18: Induction of Ab Amyloidogenesis In Vivo by Blood Transfusion
Rodrigo Morales,1,† Claudia Duran-Aniotz,1, 2 Akihiko Urayama,1 Lisbell Estrada,3 Diego Morales-Scheihing1, 2 and Claudio Soto1
1University of Texas Health Science Center at Houston; Houston, TX USA; 2Universidad de Los Andes; Santiago, Chile; 3Universidad Catolica de Chile; Santiago, Chile†Presenting author; Email: Rodrigo.MoralesLoyola@uth.tmc.edu
Alzheimer disease (AD) is the most common type of senile dementia. Disease manifestation is characterized by progressive impairment of memory and cognition which is triggered by synaptic dysfunction and neuronal loss. Compelling evidence suggests that misfolding and aggregation of Ab is a hallmark event in the disease pathogenesis. An important unanswered question related to AD involves its etiology since over 90% of the AD cases arise sporadically. Interestingly, misfolding and aggregation of proteins is the main feature of other diseases -termed Protein Misfolding Disorders (PMDs)] which include Transmissible Spongiform Encephalopathies (TSEs), among others. Convincing experimental evidences have shown that the only component of the infectious agent in TSEs is the misfolded form of the prion protein. Strikingly, the molecular mechanisms responsible for prion replication are very similar to the process of amyloid formation in all PMDs, suggesting that all these diseases have the inherent capability of being transmissible. Recent reports have shown that intra-cerebral and intra-peritoneal administration of brain homogenates containing Ab aggregates can accelerate the generation of senile plaques in mice models of AD. However, it remains to be demonstrated if this phenomenon can occur by more relevant routes of administration. The aim of this study was to assess whether AD pathogenesis can be induced intravenously, mimicking the know transmission of prion diseases through blood transfusion. For this purpose we used young tg2576 mice which were injected with blood obtained from 12 months old tg2576 mice (AD-blood) that contains a substantial quantity of cerebral Ab deposits. Mice were sacrificed at 250 days old, a time in which these animals scarcely develop Ab deposits. Interestingly, we observed that infusion of AD-blood induces substantial Ab accumulation in animals that without treatment or injected with wild type blood would barely have any detectable Ab lesion. Plaque deposition was mainly present in cortex and hippocampus, being more abundant in the former. In addition, we observed a decrease in memory in mice challenged with AD-blood. Other features such as brain inflammation and synaptic integrity were also measured. Importantly, similar results were obtained in a second and independent experiment performed in a double transgenic mouse model that develops AD plaques as early as 4 months old. Our results indicate that an AD-like pathogenesis can be induced by intravenous administration of AD-blood, presumably through induction of protein misfolding in a similar way as prion diseases. These findings may open a new avenue to understand the origin of sporadic AD and may provide new strategies for disease intervention and prevention.
PPPM.20: Prion-Like Propagation and Neurotoxicity of Recombinant a-Synuclein Aggregates Initiated by Dimerization
Alireza Roostaee† and Xavier Roucou
University of Sherbrooke; Sherbrooke, QC Canada†Presenting author; Email: email@example.com
Misfolding of the a-Synuclein (a-Syn) protein and subsequent formation of amyloid fibrils or toxic aggregates are neuropathological hallmarks of Parkinson’s Disease (PD). However, a detailed characterization of the mechanism of a-synuclein aggregation/fibrillogenesis and transmission of toxic aggregates has not yet been achieved. In this study, the rates of a-Syn aggregation were compared for wild-type (wt) as well as a chimeric form of a-Syn containing an inducible Fv dimerizing domain (a-SynFv) with the capacity to form homodimers in the presence of a divalent ligand (AP20187). Here we report the increased oligomerization and fibril formation rate of recombinant a-SynFv in the presence of AP20187, in comparison to wt a-Syn or a-SynFv in the absence of divalent ligand. In addition, dimerization of a-SynFv accelerated structural transition from random coil into b-sheet conformation, which is characteristic of a-Syn aggregates. a-SynFv oligomers, but not corresponding monomers or amyloid fibrils, induced neurotoxicity when injected into the hippocampus of wt mice. These recombinant aggregates were amplified by the protein misfolding cyclic amplification (PMCA) method, providing first evidence for the in vitro propagation of synthetic a-Syn aggregates. Our results provide direct evidence for similarities between a-Syn and prion propagation and neutoxicity at the molecular level.
Wednesday, April 27, 2011
GENERATION ALZHEIMER'S: THE DEFINING DISEASE OF THE BABY BOOMERS
Saturday, January 22, 2011
Alzheimer's, Prion, and Neurological disease, and the misdiagnosis there of, a review 2011
Friday, September 3, 2010
Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE
Thursday, December 23, 2010
Alimentary prion infections: Touch-down in the intestine, Alzheimer, Parkinson disease and TSE mad cow diseases $ The Center for Consumer Freedom