Researchers’ Discovery May Revolutionize Treatment of ALS
PrioNet Canada researchers in Vancouver confirm prion-like properties in Amyotrophic Lateral Sclerosis (ALS)
September 20, 2011 (Vancouver, BC) - A team of researchers from the University of British Columbia and the Vancouver Coastal Health Research Institute have found a key link between prions and the neurodegenerative disease ALS (Amyotrophic Lateral Sclerosis), also known as Lou Gehrig’s disease. The discovery is significant as it opens the door to novel approaches to the treatment of ALS.
A pivotal paper published by the team this week in the Proceedings of the National Academy of Sciences (PNAS), demonstrates that the SOD1 protein (superoxide dismutase 1), which has been shown to be implicated in the ALS disease process, exhibits prion-like properties. The researchers found that SOD1 participates in a process called template-directed misfolding. This term refers to the coercion of one protein by another protein to change shape and accumulate in large complexes in a fashion similar to the process underlying prion diseases.
These findings provide a molecular explanation for the progressive spread of ALS through the nervous system, and highlight the central role of the propagation of misfolded proteins in the pathogenesis of neurodegenerative diseases, including ALS, Alzheimer’s and Parkinson’s.
“Our work has identified a specific molecular target, which when manipulated halts the conversion of the SOD1 protein to a misfolded, disease-causing form,” says Dr. Neil Cashman, Scientific Director of PrioNet Canada, Canada Research Chair in Neurodegeneration and Protein Misfolding at UBC, and academic director of the Vancouver Coastal Health ALS Centre. “This discovery is a first-step toward the development of targeted treatments that may stop progression of ALS.”
ALS is a progressive neuromuscular disease in which nerve cells die, resulting in paralysis and death. Approximately 2,500 to 3,000 Canadians currently live with this fatal disease, for which there is no effective treatment yet.
“For many years, ALS has remained a complex puzzle and we have found a key piece to help guide the research community to solutions,” says Dr. Leslie Grad, a co-first author of the project and current Manager of Scientific Programs at PrioNet Canada. “PrioNet is further exploring this discovery through newly-funded research projects.”
The work was completed by Dr. Neil Cashman’s lab at the Brain Research Centre based at the University of British Columbia and the Vancouver Coastal Health Research Institute, in collaboration with researchers at the University of Alberta. The research was supported by PrioNet Canada and in part by Amorfix Life Sciences and the Canadian Institutes of Health Research.
PrioNet Canada, based in Vancouver, has achieved international attention for scientific discoveries and risk management strategies directed at controlling prion diseases, and is now directing capacity into therapeutic solutions for prion-like diseases of aging, such as Alzheimer’s, Parkinson’s and ALS.
About: One of Canada’s Networks of Centres of Excellence, PrioNet Canada (www.prionetcanada.ca) is developing strategies to help solve the food, health safety, and socioeconomic problems associated with prion diseases. The network brings together scientists, industry, and public sector partners through its multidisciplinary research projects, training programs, events, and commercialization activities. PrioNet is hosted by the University of British Columbia and the Vancouver Coastal Health Research Institute in Vancouver.
The University of British Columbia (UBC) is one of North America’s largest public research and teaching institutions, and one of only two Canadian institutions consistently ranked among the world’s 40 best universities. UBC is a place that inspires bold, new ways of thinking that have helped make it a national leader in areas as diverse as community service learning, sustainability and research commercialization. UBC offers more than 50,000 students a range of innovative programs and attracts $550 million per year in research funding from government, non-profit organizations and industry through 7,000 grants.
Vancouver Coastal Health Research Institute (VCHRI) (www.vchri.ca) is the research body of Vancouver Coastal Health Authority, which includes BC’s largest academic and teaching health sciences centres: VGH, UBC Hospital, and GF Strong Rehabilitation Centre. In academic partnership with the University of British Columbia, VCHRI brings innovation and discovery to patient care, advancing healthier lives in healthy communities across British Columbia, Canada, and beyond.
The Brain Research Centre comprises more than 200 investigators with multidisciplinary expertise in neuroscience research ranging from the test tube, to the bedside, to industrial spin-offs. The centre is a partnership of UBC and Vancouver Coastal Health Research Institute. For more information, visit www.brain.ubc.ca.
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Media information or to set up interviews: Gail Bergman, Gail Bergman PR Tel: (905) 886-1340 or (905) 886-3345 E-mail: firstname.lastname@example.org
Backgrounder - ALS as a "prion-like" disease
Amyotrophic lateral sclerosis (ALS): Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig ’s disease in the United States and motor neurone disease (MND) in Europe, is a fatal neurodegenerative disease caused by deterioration of motor neurons in the brain and spinal cord. Individuals living with the disease experience progressive paralysis, as well as difficulty breathing or swallowing. At this time, no cure or effective treatment exists.
According to the ALS Society of Canada: • ALS is the most common cause of neurological death • Every day two or three Canadians die of ALS • Eighty per cent of people with ALS die within two to five years of diagnosis; ten per cent of those affected may live for 10 years or longer • Approximately 2,500 - 3,000 Canadians currently live with this fatal disease • The World Health Organization predicts that neurodegenerative diseases will surpass cancer as the second leading cause of death in Canada by 2040
Background: Recent research highlights links between the biological mechanisms of common neurological disorders, such as ALS, Alzheimer’s and Parkinson’s disease with prion disease. While each of these diseases manifests itself in a different way, the hallmark of each is a progressive accumulation of misfolded protein aggregates in the central nervous system.
Correctly-folded proteins adopt one particular structure in order to carry out their intended function. A protein’s failure to adopt this correct structure is what threatens the health of cells. Prions are “misfolded” proteins -- the infectious, aggregating agents in diseases such as Creutzfeldt-Jakob disease (CJD) in humans, chronic wasting disease (CWD) in deer and elk and bovine spongiform encephalopathy (BSE), also known as “mad cow” disease in cattle. In ALS, Alzheimer’s and Parkinson’s, the misfolded proteins are SOD1, amyloid-ß, and a-synuclein, respectively.
Key Finding: “Intermolecular transmission of SOD-1 misfolding in living cells” - Published in the Proceedings of the National Academy of Sciences (PNAS), September 2011 • The paper shows that superoxide dismutase 1 (SOD1) participates in template-directed misfolding, in other words, the coercion of one protein by another protein to change shape and aggregate such as prion diseases do. • The results will be significant to the ALS field because it connects prion mechanisms behind the biological progression of ALS, and provides a molecular explanation for the linear and temporal spread of ALS through the nervous system. • Furthermore, the research has identified a specific molecular target, which when manipulated, halts the conversion of SOD1 to a misfolded, disease-causing form. This is a first-step towards the development of targeted treatments that may stop ALS, which PrioNet is further exploiting through newly-funded research. • This research was supported by PrioNet Canada and in part by Amorfix Life Sciences and the Canadian Institutes of Health Research.
Other Research: Studies showing how “seed” misfolded protein induce aggregation of other protein, which provide evidence for prion-like spread: • Lary Walker’s group at Emory University in Atlanta, in collaboration with Matthias Jucker and others at the Universities of Tübingen in Germany and Basel in Switzerland, discovered that aggregates of amyloid-ß protein from the brain of people with Alzheimer’s disease could be transmitted to the brain of healthy mice. • Another study by Patrik Brundin’s group in Sweden demonstrated that healthy tissue surgically implanted into the brain of people with Parkinson’s disease acquired the aggregates of a-synuclein protein characteristic of the disease. • Eliezer Masliah of the University of California San Diego and others discovered that aggregates of a-synuclein can travel from cell to cell, forming the aggregates in human neurons that are characteristic of Parkinson’s disease and certain types of dementia. • Anne Bertolotti from the University of Cambridge discovered that neuronal cells spontaneously and efficiently take up misfolded mutant SOD1 from their environment. The internalized mutant SOD1 triggers a change in shape of the normally soluble mutant SOD1 protein, which causes its aggregation, and is then transferred to neighbouring cells in a prion-like fashion.
Last Updated: 9/20/2011 3:19:45 PM
Intermolecular transmission of superoxide dismutase 1 misfolding in living cells
Leslie I. Grada,1, Will C. Guesta,1, Anat Yanaia, Edward Pokrishevskya, Megan A. O'Neilla, Ebrima Gibbsa, Valentyna Semenchenkob, Masoud Yousefia, David S. Wishartc, Steven S. Plotkind, and Neil R. Cashmana,2
+ Author Affiliations
aBrain Research Centre, University of British Columbia, Vancouver, BC, Canada V6T 2B5;
bNational Institute for Nanotechnology, Edmonton, AB, Canada T6G 2M9;
cDepartments of Biological Sciences and Computing Science, University of Alberta, Edmonton, AB, Canada, T6G 2E8; and
dDepartment of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada V6T 1Z1
Edited* by Don W. Cleveland, University of California at San Diego, La Jolla, CA, and approved July 25, 2011 (received for review February 23, 2011)
Human wild-type superoxide dismutase-1 (wtSOD1) is known to coaggregate with mutant SOD1 in familial amyotrophic lateral sclerosis (FALS), in double transgenic models of FALS, and in cell culture systems, but the structural determinants of this process are unclear. Here we molecularly dissect the effects of intracellular and cell-free obligately misfolded SOD1 mutant proteins on natively structured wild-type SOD1. Expression of the enzymatically inactive, natural familial ALS SOD1 mutations G127X and G85R in human mesenchymal and neural cell lines induces misfolding of wild-type natively structured SOD1, as indicated by: acquisition of immunoreactivity with SOD1 misfolding-specific monoclonal antibodies; markedly enhanced protease sensitivity suggestive of structural loosening; and nonnative disulfide-linked oligomer and multimer formation. Expression of G127X and G85R in mouse cell lines did not induce misfolding of murine wtSOD1, and a species restriction element for human wtSOD1 conversion was mapped to a region of sequence divergence in loop II and ß-strand 3 of the SOD1 ß-barrel (residues 24–36), then further refined surprisingly to a single tryptophan residue at codon 32 (W32) in human SOD1. Time course experiments enabled by W32 restriction revealed that G127X and misfolded wtSOD1 can induce misfolding of cell-endogenous wtSOD1. Finally, aggregated recombinant G127X is capable of inducing misfolding and protease sensitivity of recombinant human wtSOD1 in a cell-free system containing reducing and chelating agents; cell-free wtSOD1 conversion was also restricted by W32. These observations demonstrate that misfolded SOD1 can induce misfolding of natively structured wtSOD1 in a physiological intracellular milieu, consistent with a direct protein–protein interaction.
Supporting Information Grad et al. 10.1073/pnas.1102645108 SI Materials and Methods
Saturday, January 22, 2011
Alzheimer's, Prion, and Neurological disease, and the misdiagnosis there of, a review 2011
Tuesday, June 7, 2011
Protein aggregate spreading in neurodegenerative diseases: Problems and perspectives
IN STRICT CONFIDENCE
Dr McGovern From: Dr A Wight
Date: 5 January 1993
Copies: Dr Metters
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC.
2. Briefly, the meeting agreed that:
i) Dr Ridley et als findings of experimental induction of p amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegenerative disorders;
ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and
iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion.
5 NOV 1992
CMO From: Dr J S Metters DCMO 4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have recognized the public sensitivity of these findings and intend to report them in their proper context. This hopefully will avoid misunderstanding and possible distortion by the media to portray the results as having more greater significance than the findings so far justify.
2. Using a highly unusual route of transmission (intra-cerebral injection) the researchers have demonstrated the transmission of a pathological process from two cases one of severe Alzheimer's disease the other of Gerstmann-Straussler disease to marmosets. However they have not demonstrated the transmission of either clinical condition as the "animals were behaving normally when killed'. As the report emphasizes the unanswered question is whether the disease condition would have revealed itself if the marmosets had lived longer. They are planning further research to see if the conditions, as opposed to the partial pathological process, is transmissible.
What are the implications for public health?
3. . The route of transmission is very specific and in the natural state of things highly unusual. However it could be argued that the results reveal a potential risk, in that brain tissue from these two patients has been shown to transmit a pathological process. Should therefore brain tissue from such cases be regarded as potentially infective? Pathologists, morticians, neuro surgeons and those assisting at neuro surgical procedures and others coming into contact with "raw" human brain tissue could in theory be at risk. However, on a priori grounds given the highly specific route of transmission in these experiments that risk must be negligible if the usual precautions for handling brain tissue are observed.
4. The other dimension to consider is the public reaction. To some extent the GSS case demonstrates little more than the transmission of BSE to a pig by intra-cerebral injection. If other prion diseases can be transmitted in this way it is little surprise that some pathological findings observed in GSS were also transmissible to a marmoset. But the transmission of features of Alzheimer's pathology is a different matter, given the much greater frequency of this disease and raises the unanswered question whether some cases are the result of a transmissible prion. The only tenable public line will be that "more research is required" before that hypothesis could be evaluated. The possibility on a transmissible prion remains open. In the meantime MRC needs carefully to consider the range and sequence of studies needed to follow through from the preliminary observations in these two cases. Not a particularly comfortable message, but until we know more about the causation of Alzheimer's disease the total reassurance is not practical.
JS METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832
Wednesday, April 27, 2011
GENERATION ALZHEIMER'S: THE DEFINING DISEASE OF THE BABY BOOMERS
what are they going to do with all us baby boomers by 2050 where an estimated 13.5 million Americans will be stricken with Alzheimer's, up from 5 million plus ? what about the non paid caregivers of these Alzheimer's figures, where by 2050, these figures for caregivers will rise as well, to some 20 million, if we are all still here ? sadly, to add to all this misery, the price of poker is going up too. i apologize for my mood, but i am mad about all these cuts. they have cut funding for prion disease to ZERO DOLLARS!
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.
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
Wednesday, January 5, 2011
ENLARGING SPECTRUM OF PRION-LIKE DISEASES Prusiner Colby et al 2011 Prions
David W. Colby1,* and Stanley B. Prusiner1,2
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
Wednesday, August 24, 2011
There Is No Safe Dose of Prions
Thursday, August 4, 2011
Terry Singeltary Sr. on the Creutzfeldt-Jakob Disease Public Health Crisis, Date aired: 27 Jun 2011
Sunday, August 21, 2011
The British disease, or a disease gone global, The TSE Prion Disease