ENLARGING SPECTRUM OF PRION-LIKE DISEASES Prusiner Colby et al 2011

Prions

David W. Colby1,* and Stanley B. Prusiner1,2

+ Author Affiliations

1Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California 94143 2Department of Neurology, University of California, San Francisco, San Francisco, California 94143 Correspondence: stanley@ind.ucsf.edu


Abstract


The discovery of infectious proteins, denoted prions, was unexpected. After much debate over the chemical basis of heredity, resolution of this issue began with the discovery that DNA, not protein, from pneumococcus was capable of genetically transforming bacteria ( Avery et al. 1944). Four decades later, the discovery that a protein could mimic viral and bacterial pathogens with respect to the transmission of some nervous system diseases ( Prusiner 1982) met with great resistance. Overwhelming evidence now shows that Creutzfeldt–Jakob disease (CJD) and related disorders are caused by prions. The prion diseases are characterized by neurodegeneration and lethality. In mammals, prions reproduce by recruiting the normal, cellular isoform of the prion protein (PrPC) and stimulating its conversion into the disease-causing isoform (PrPSc). PrPC and PrPSc have distinct conformations: PrPC is rich in a-helical content and has little ß-sheet structure, whereas PrPSc has less a-helical content and is rich in ß-sheet structure ( Pan et al. 1993). The conformational conversion of PrPC to PrPSc is the fundamental event underlying prion diseases. In this article, we provide an introduction to prions and the diseases they cause.


snip...


HUMAN PRION DISEASES


Prion diseases occur as sporadic, genetic, and transmissible disease in humans (Table 1). Although infectious forms of prion disease are most well known to the general public, sporadic and heritable forms of the disease occur much more frequently in humans, with sporadic (s) CJD accounting for approximately 85% of cases. sCJD has no known cause although spontaneous misfolding of PrPC into PrPSc is a leading hypothesis (Prusiner 1989; Hsiao et al. 1991a). Alternate hypotheses include somatic mutation of PRNP, undetected horizontal transmission (Gajdusek 1977), and infrequent amplification of low levels of PrPSc that are part of “normal” protein homeostasis. The brains of sCJD patients harbor infectious prions that are transmissible to experimental animals (Gibbs et al. 1968; Brown et al. 1994). In humans, virtually all forms of prion disease feature neuropathological changes including vacuolation (resulting in the spongiform appearance of brain tissue), astrocytic gliosis, and PrP deposition. The morphology of vacuoles and PrP deposits varies depending on the prion strain and host, as do the regions of the brain affected.


Prion diseases in humans and animals.


To date, over 40 different mutations of the PrP gene have been shown to segregate with the heritable human prion diseases (Fig. 2). The resulting diseases have been classified as Gerstmann–Sträussler–Scheinker syndrome (GSS), familial (f) CJD, or fatal familial insomnia (FFI) according to the clinical symptoms, although all result from PRNP mutations. At the time when the discoveries were reported that fCJD and GSS could be transmitted to apes and monkeys, many still thought that scrapie, CJD, and related disorders were caused by slow viruses (Roos et al. 1973; Masters et al. 1981). Only the discovery that a proline-to-leucine mutation at codon 102 of the human PrP gene was genetically linked to some GSS pedigrees permitted the unprecedented conclusion that prion disease can have both genetic and infectious etiologies (Hsiao et al. 1989; Prusiner 1989). This mutation has been found in unrelated families from several countries (Doh-ura et al. 1989; Goldgaber et al. 1989; Kretzschmar et al. 1991), and other mutations causing GSS have since been identified (Dlouhy et al. 1992; Petersen et al. 1992; Poulter et al. 1992; Rosenmann et al. 1998).


Likewise, several different mutations have also been discovered to cause fCJD. A repeat expansion in the amino-terminal region of PrP, which in the healthy population contains five repetitive sequences of eight residues each (octarepeats), has been genetically linked to fCJD. Insertions of two to nine additional octarepeats have been found in individuals within fCJD pedigrees (Owen et al. 1989; Goldfarb et al. 1991a). Molecular genetic investigations have revealed that Libyan and Tunisian Jews with fCJD have a PrP gene point mutation at codon 200, resulting in a glutamic acid-to-lysine substitution (Goldfarb et al. 1990a; Hsiao et al. 1991b), a mutation that has since been identified in fCJD pedigrees in many locations (Goldfarb et al. 1990a; Goldfarb et al. 1990b; Bertoni et al. 1992).


The D178N mutation can cause either fCJD or FFI, depending on the polymorphism present at codon 129, where both methionine and valine are commonly found. D178N coupled with V129 produces fCJD, in which patients present with dementia and widespread deposition of PrPSc (Goldfarb et al. 1991c). If the disease mutation is coupled with M129, however, FFI results and patients present with a progressive sleep disorder that is ultimately fatal. Postmortem analysis of FFI brains revealed deposition of PrPSc confined largely to specific regions of the thalamus (Lugaresi et al. 1986; Gambetti et al. 1995).


Infectious forms of prion diseases include kuru, iatrogenic (i) CJD, and variant (v) CJD. Kuru in the highlands of New Guinea was transmitted by ritualistic cannibalism, as people in the region ate the brains of their dead relatives in an attempt to immortalize them (Glasse 1967; Alpers 1968; Gajdusek 1977). Iatrogenic transmissions include prion-tainted human growth hormone and gonadotropin, dura mater grafts, and transplants of corneas obtained from people who died of CJD (Koch et al. 1985; PHS 1997). In addition, CJD cases have been recorded after neurosurgical procedures in which ineffectively sterilized depth electrodes or instruments were used.


More than 200 teenagers and young adults have died of vCJD, mostly in Britain (Spencer et al. 2002; Will 2003). Both epidemiologic and experimental studies have built a convincing case that vCJD resulted from prions being transmitted from cattle with bovine spongiform encephalopathy (BSE, or “mad cow” disease) to humans through consumption of contaminated beef products (Chazot et al. 1996; Will et al. 1996; Cousens et al. 1997). Until recently, all of the vCJD-affected individuals were identified to express methionine homozygously at codon 129. A single case of vCJD in a patient heterozygous at codon 129 has been reported, raising the possibility of a second wave of “mad cow”–related deaths (Kaski et al. 2009).


PRION DISEASES OF ANIMALS


Prion diseases occur naturally in many mammals, including scrapie of sheep and goats, BSE, transmissible mink encephalopathy (TME), chronic wasting disease (CWD) of mule deer and elk, feline spongiform encephalopathy, and exotic ungulate encephalopathy (Table 1). Unlike in humans, prion diseases in animals mainly occur as infectious disorders. As in humans, prion disease in animals is characterized by neuropathologic changes, including vacuolation, astrocytic gliosis, and PrP deposition.


Scrapie of sheep has been documented in Europe for hundreds of years. Despite efforts attempting to link scrapie to CJD, no evidence exists to establish a relationship (Chatelain et al. 1981). Polymorphisms in sheep PrP modulate susceptibility to scrapie, rendering some breeds more resistant to infection than others (Goldmann et al. 1991). As scrapie prions can persist in soil for years (Palsson 1979; Brown and Gajdusek 1991), selective breeding programs may be the most effective means to eradicate scrapie. In part because scrapie is not infectious for humans, hamster- and mouse-adapted scrapie strains, such as Sc237 and RML, are important laboratory tools for studying prions.


During the BSE epidemic in Britain, it was estimated that nearly one million cattle were infected with prions (Anderson et al. 1996; Nathanson et al. 1997). The mean incubation time for BSE is approximately 5 years. Most cattle were slaughtered between 2 and 3 years of age, and therefore, in a presymptomatic phase of infection (Stekel et al. 1996). BSE is a massive common-source epidemic caused by meat and bone meal (MBM) fed primarily to dairy cows (Wilesmith et al. 1991; Nathanson et al. 1997). MBM was prepared from the offal of sheep, cattle, pigs, and chickens as a high-protein nutritional supplement. In the late 1970s, the hydrocarbon-solvent extraction method used in the rendering of offal began to be abandoned, resulting in MBM with a much higher fat content (Wilesmith et al. 1991; Muller et al. 2007). It is now thought that this change allowed scrapie prions from sheep or low levels of bovine prions generated sporadically to survive the rendering process, resulting in the widespread infection of cattle. Changes in the methods used for feeding cattle have since eliminated the epidemic, although sporadic BSE cases arise occasionally.


Mule deer, white-tailed deer, and elk have been reported to develop CWD. As the only prion disease identified in free-ranging animals, CWD appears to be far more communicable than other forms of prion disease. CWD was first described in 1967 and was reported to be a spongiform encephalopathy in 1978 on the basis of histopathology of the brain. Originally detected in the American West, CWD has spread across much of North America and has been reported also in South Korea. In captive populations, up to 90% of mule deer have been reported to be positive for prions (Williams and Young 1980). The incidence of CWD in cervids living in the wild has been estimated to be as high as 15% (Miller et al. 2000). The development of transgenic (Tg) mice expressing cervid PrP, and thus susceptible to CWD, has enhanced detection of CWD and the estimation of prion titers (Browning et al. 2004; Tamgüney et al. 2006). Shedding of prions in the feces, even in presymptomatic deer, has been identified as a likely source of infection for these grazing animals (Williams and Miller 2002; Tamgüney et al. 2009b). CWD has been transmitted to cattle after intracerebral inoculation, although the infection rate was low (4 of 13 animals [Hamir et al. 2001]). This finding raised concerns that CWD prions might be transmitted to cattle grazing in contaminated pastures.


snip...


PRION STRAINS


Naturally occurring prion strains have been isolated, each with a distinct incubation period and characteristic pathology; these traits are often conserved on serial transmission (Dickinson and Meikle 1969; Fraser and Dickinson 1973). Because prions are composed only of protein and replicate using the PrP substrate present in the host, differences in prion strains cannot be attributed to genetic variability, which accounts for the existence of viral strains. Rather, prion strains arise from conformational variability—that is, PrP can assume several different, self-propagating conformations, each of which enciphers a distinct prion strain. Biochemical evidence (Bessen and Marsh 1994; Collinge et al. 1996; Telling et al. 1996; Peretz et al. 2001a) and recent studies with synthetic prions support this theory (Colby et al. 2009).


Studies with synthetic prions showed that the mouse synthetic prion (MoSP) strain 1 gradually adopted properties associated with naturally occurring prion strains such as RML, including short incubation times and low conformational stabilities (Ghaemmaghami et al., in prep.). These changes were accompanied by a structural transformation, as indicated by a shift in the molecular mass of the protease-resistant core of MoSP1 from approximately 19 kDa [MoSP1(2)] to 21 kDa [MoSP1(1)]. We found that MoSP1(1) and MoSP1(2) could be bred with fidelity when cloned in N2a cells but when present as a mixture, MoSP1(1) propagation led to the disappearance of MoSP1(2). In culture, the rate of this transformation could be modified by the culture media and the presence of polyamidoamines. These findings showed that prions exist as conformationally diverse populations and each strain can replicate with high fidelity. Competition and selection among the pool of strains provide a mechanism for prion transformation and adaptation (Li et al. 2010).


Yeast also show multiple prion strains. A recombinant Sup35 protein fragment refolded into two different conformations was shown to initiate two distinct [PSI+] strain phenotypes on transduction into yeast (King and Diaz-Avalos 2004; Tanaka et al. 2004). The propagation rates for these synthetic yeast prion strains were coupled to their conformational stability (Tanaka et al. 2004), a finding that was later extended to mammalian prion strains (Legname et al. 2006; Colby et al. 2009).


ENLARGING SPECTRUM OF PRION-LIKE DISEASES


The discovery that prions form amyloid prompted one of us to suggest that the common neurodegenerative diseases are also caused by prions (Prusiner 1984; Prusiner 2001) despite the inability to transmit such illnesses to monkeys and apes (Goudsmit et al. 1980). Brain extracts from either Alzheimer's patients or aged Tg mice expressing mutant APP injected into the brains of Tg mice expressing the amyloid precursor protein (APP) carrying the Swedish point mutation (Haass et al. 1995) accelerated the formation of Aß amyloid plaques (Meyer-Luehmann et al. 2006; Eisele et al. 2009). Brain extracts from Tg mice expressing mutant tau injected into the brains of Tg mice expressing human wt tau produced aggregates of human tau (Clavaguera et al. 2009). Similar results were found for aggregated tau protein added to cultured cells, which induced the aggregation of nascent tau (Frost et al. 2009). These findings suggest that the tauopathies result from a prion-like process that induces hyperphosphorylation of tau followed by polymerization into filamentous aggregates. The production of hyperphosphorylated tau also appears to be stimulated by oligomers of the Aß peptide, whereas amyloid fibrils comprised of Aß are a much less efficient stimulus (Lambert et al. 1998). An expanded 44-mer polyglutamine repeat of a truncated huntingtin protein was found to stimulate aggregation of a “normal” 25 mer; this aggregated state could be maintained in cell culture over many generations, arguing for prion-like propagation of huntingtin aggregates (Ren et al. 2009). Patients suffering from Parkinson's disease who received fetal grafts of substantia nigral cells later showed aberrantly folded a-synuclein in Lewy bodies within the transplanted grafts, arguing that a-synuclein acted like a prion (Kordower et al. 2008; Li et al. 2008; Olanow and Prusiner 2009). Taken together, these findings argue that prion-like, self-propagating states feature in many different, if not all, neurodegenerative diseases.


A general model of propagation of mammalian prion-like conformational states should include the following considerations (Table 2): First, when the precursor protein is converted to a prion, it undergoes posttranslational modification. Such changes generally result in the acquisition of a high ß-sheet content. Proteolytic cleavage features in Alzheimer's disease (AD) (Glenner and Wong 1984; Masters et al. 1985) and hyperphosphorylation occurs in both AD and the tauopathies (Grundke-Iqbal et al. 1986; Lee et al. 1991). Second, the ß-sheet–rich conformers form oligomers that are toxic to cells (Walsh and Selkoe 2007). Third, such oligomers are generally rendered less toxic when they polymerize into amyloid fibrils. Fourth, amyloid fibrils are sequestered into biological wastebaskets in the CNS where they are designated “plaques” in the extracellular space, and “tangles” or “bodies” within the cytoplasm of neurons. Inert PrP amyloid fibrils coalesce to form plaques in prion diseases whereas fibrils composed of the Aß peptide form plaques in AD. Paired-helical filaments composed of hyperphosphorylated tau form neurofibrillary tangles in AD, whereas tau fibrils coalesce into deposits called Pick bodies in one of the frontotemporal dementias generally labeled Pick's disease. In other tauopathies, less well-formed tau aggregates have been identified inside cells. After a-synuclein acquires a high ß-sheet content, it polymerizes into amyloid fibrils that coalesce in neurons to form Lewy bodies. Fifth, mutations in the corresponding proteins cause familial neurodegenerative diseases and facilitate conversion of the protein to its prion state. For example, over 40 mutations in PrP have been identified that cause GGS, fCJD, and FFI (Hsiao et al. 1989; Goldfarb et al. 1991b; Medori et al. 1992). Mutations in APP or presenilin (?-secretase) that cleaves APP into Aß cause familial AD (Goate et al. 1991), and duplication of the APP gene in Down's syndrome invariably causes AD (Goldgaber et al. 1987). Mutations in tau cause tauopathies (Hutton et al. 1998). Mutations in a-synuclein cause familial Parkinson's disease (Polymeropoulos et al. 1997); duplication or triplication of the a-synuclein gene also causes Parkinson's disease (Singleton et al. 2003).


Prions need not cause disease but may function as regulators of cell metabolism. In yeast, all of the prion proteins found to date have a CG-rich domain that adopts a ß-sheet–rich conformation that polymerizes into amyloid. The Sup35 protein in the prion state causes a reduction in the fidelity of polypeptide chain termination during protein synthesis (Wickner et al. 2007). The Aplysia prion comprised of the cytoplasmic polyadenylation element binding (CPEB) protein appears to facilitate polyadenylation within limited regions of neuronal cells, such as dendrites, and has been suggested to function in long-term memory (Si et al. 2010).


snip...


TOWARD THERAPEUTICS FOR PRION DISEASES


Despite these advances in understanding prions and many of the neurodegenerative diseases, no treatment is currently available to halt the progression of any of these illnesses. Studies of prions in mice have elucidated several aspects of neurodegeneration that may prove useful in developing effective therapeutics. First, reduction of the precursor protein PrPC prolongs the incubation time (Büeler et al. 1993; Prusiner et al. 1993; Safar et al. 2005). Second, slowing prion formation by inhibiting of the formation of nascent PrPSc prolongs the incubation time (Kawasaki et al. 2007). Third, reducing the availability of PrPC in cells or mice where prion infection has already been established allows for existing prions to be cleared (Enari et al. 2001; Peretz et al. 2001b; Safar et al. 2005). Fourth, enhancing the clearance of PrPSc provides an alternative route of action for therapeutic intervention (Supattapone et al. 1999b; Supattapone et al. 2001).


Blocking conversion of PrPC to PrPSc would seem to be the most practical therapeutic approach, as the cellular pathogenesis of prion disease is downstream of this event and not well understood. Many compounds that inhibit conversion have been identified, including polysulfated anions, dextrans, Congo red dye, oligonucleotides, and cyclic tetrapyrroles (for reviews, see Trevitt and Collinge [2006]; Sim and Caughey [2009]; Silber [2010]). Effective treatment for prion disease is hampered by the difficulty of these and other putative therapeutics to access the CNS, and by the difficulty of identifying small molecules that can prevent the protein–protein interactions that result in propagation of alternatively folded protein isoforms. Studies with a phenylhydrazone revealed restricted efficacy for specific prion strains (Kawasaki et al. 2007) whereas studies with the drug quinacrine revealed the development of drug-resistant prions (Ghaemmaghami et al. 2009).


It seems likely that studies on therapeutics for prion diseases will inform the development of drugs that halt AD, the frontotemporal dementias, or Parkinson's disease; moreover, the lack of success in treating such diseases argues for new paradigms. Work on the prion diseases suggests that treatment for a limited time that reduces or interrupts the formation of nascent prions may be sufficient for the normal cellular clearance mechanisms to overtake the synthesis of new prions. Such an approach would argue for the development of drugs that can be administered for a short period of time instead of many years, which is the commonly held supposition.


snip...please see full text here ;



http://cshperspectives.cshlp.org/content/3/1/a006833.full.html#ref-24




CWD to cattle figures CORRECTION


Greetings,


I believe the statement and quote below is incorrect ;



"CWD has been transmitted to cattle after intracerebral inoculation, although the infection rate was low (4 of 13 animals [Hamir et al. 2001]). This finding raised concerns that CWD prions might be transmitted to cattle grazing in contaminated pastures."



Please see ;




Within 26 months post inoculation, 12 inoculated animals had lost weight, revealed abnormal clinical signs, and were euthanatized. Laboratory tests revealed the presence of a unique pattern of the disease agent in tissues of these animals. These findings demonstrate that when CWD is directly inoculated into the brain of cattle, 86% of inoculated cattle develop clinical signs of the disease.



http://www.ars.usda.gov/research/publications/publications.htm?seq_no_115=194089





" although the infection rate was low (4 of 13 animals [Hamir et al. 2001]). "




shouldn't this be corrected, 86% is NOT a low rate. ...




kindest regards,


Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518




Thank you!

Thanks so much for your updates/comments. We intend to publish as rapidly as possible all updates/comments that contribute substantially to the topic under discussion.



http://cshperspectives.cshlp.org/letters/submit




re-Prions David W. Colby1,* and Stanley B. Prusiner1,2 + Author Affiliations

1Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California 94143 2Department of Neurology, University of California, San Francisco, San Francisco, California 94143 Correspondence: stanley@ind.ucsf.edu


http://cshperspectives.cshlp.org/content/3/1/a006833.full.pdf+html




Mule deer, white-tailed deer, and elk have been reported to develop CWD. As the only prion disease identified in free-ranging animals, CWD appears to be far more communicable than other forms of prion disease. CWD was first described in 1967 and was reported to be a spongiform encephalopathy in 1978 on the basis of histopathology of the brain. Originally detected in the American West, CWD has spread across much of North America and has been reported also in South Korea. In captive populations, up to 90% of mule deer have been reported to be positive for prions (Williams and Young 1980). The incidence of CWD in cervids living in the wild has been estimated to be as high as 15% (Miller et al. 2000). The development of transgenic (Tg) mice expressing cervid PrP, and thus susceptible to CWD, has enhanced detection of CWD and the estimation of prion titers (Browning et al. 2004; Tamgüney et al. 2006). Shedding of prions in the feces, even in presymptomatic deer, has been identified as a likely source of infection for these grazing animals (Williams and Miller 2002; Tamgüney et al. 2009b). CWD has been transmitted to cattle after intracerebral inoculation, although the infection rate was low (4 of 13 animals [Hamir et al. 2001]). This finding raised concerns that CWD prions might be transmitted to cattle grazing in contaminated pastures.


snip...


http://cshperspectives.cshlp.org/content/3/1/a006833.full.pdf+html




please see CWD potential to humans here ;


http://betaamyloidcjd.blogspot.com/2011/01/enlarging-spectrum-of-prion-like.html




Greetings,


I believe the statement and quote below is incorrect ;



"CWD has been transmitted to cattle after intracerebral inoculation, although the infection rate was low (4 of 13 animals [Hamir et al. 2001]). This finding raised concerns that CWD prions might be transmitted to cattle grazing in contaminated pastures."



Please see ;




Within 26 months post inoculation, 12 inoculated animals had lost weight, revealed abnormal clinical signs, and were euthanatized. Laboratory tests revealed the presence of a unique pattern of the disease agent in tissues of these animals. These findings demonstrate that when CWD is directly inoculated into the brain of cattle, 86% of inoculated cattle develop clinical signs of the disease.



http://www.ars.usda.gov/research/publications/publications.htm?seq_no_115=194089




"although the infection rate was low (4 of 13 animals [Hamir et al. 2001])."



shouldn't this be corrected, 86% is NOT a low rate. ...




kindest regards,

Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518



MARCH 1, 2011

UPDATED CORRESPONDENCE FROM AUTHORS OF THIS STUDY I.E. COLBY, PRUSINER ET AL, ABOUT MY CONCERNS OF THE DISCREPANCY BETWEEN THEIR FIGURES AND MY FIGURES OF THE STUDIES ON CWD TRANSMISSION TO CATTLE ;



----- Original Message -----

From: David Colby

To: flounder9@verizon.net

Cc: stanley@XXXXXXXX

Sent: Tuesday, March 01, 2011 8:25 AM

Subject: Re: FW: re-Prions David W. Colby1,* and Stanley B. Prusiner1,2 + Author Affiliations



Dear Terry Singeltary,

Thank you for your correspondence regarding the review article Stanley Prusiner and I recently wrote for Cold Spring Harbor Perspectives. Dr. Prusiner asked that I reply to your message due to his busy schedule. We agree that the transmission of CWD prions to beef livestock would be a troubling development and assessing that risk is important. In our article, we cite a peer-reviewed publication reporting confirmed cases of laboratory transmission based on stringent criteria. The less stringent criteria for transmission described in the abstract you refer to lead to the discrepancy between your numbers and ours and thus the interpretation of the transmission rate. We stand by our assessment of the literature--namely that the transmission rate of CWD to bovines appears relatively low, but we recognize that even a low transmission rate could have important implications for public health and we thank you for bringing attention to this matter.

Warm Regards,
David Colby

--

David Colby, PhDAssistant ProfessorDepartment of Chemical EngineeringUniversity of Delaware



====================END...TSS==============




re-ENLARGING SPECTRUM OF PRION-LIKE DISEASES Prusiner Colby et al 2011 Prions




CWD to cattle figures CORRECTION


Greetings,


I believe the statement and quote below is incorrect ;



"CWD has been transmitted to cattle after intracerebral inoculation, although the infection rate was low (4 of 13 animals [Hamir et al. 2001]). This finding raised concerns that CWD prions might be transmitted to cattle grazing in contaminated pastures."



Please see ;




Within 26 months post inoculation, 12 inoculated animals had lost weight, revealed abnormal clinical signs, and were euthanatized. Laboratory tests revealed the presence of a unique pattern of the disease agent in tissues of these animals. These findings demonstrate that when CWD is directly inoculated into the brain of cattle, 86% of inoculated cattle develop clinical signs of the disease.



http://www.ars.usda.gov/research/publications/publications.htm?seq_no_115=194089



"although the infection rate was low (4 of 13 animals [Hamir et al. 2001])."



shouldn't this be corrected, 86% is NOT a low rate. ...




kindest regards,

Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518




Thank you!

Thanks so much for your updates/comments. We intend to publish as rapidly as possible all updates/comments that contribute substantially to the topic under discussion.



http://cshperspectives.cshlp.org/letters/submit





re-Prions David W. Colby1,* and Stanley B. Prusiner1,2 + Author Affiliations

1Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California 94143 2Department of Neurology, University of California, San Francisco, San Francisco, California 94143 Correspondence: stanley@ind.ucsf.edu


http://cshperspectives.cshlp.org/content/3/1/a006833.full.pdf+html





snip...full text ;





Wednesday, January 5, 2011

ENLARGING SPECTRUM OF PRION-LIKE DISEASES Prusiner Colby et al 2011 Prions

David W. Colby1,* and Stanley B. Prusiner1,2



http://cshperspectives.cshlp.org/content/3/1/a006833.full.html#ref-24





-------- Original Message --------


Subject: Re: CWD TO CATTLE by inoculation (ok,is it three or four OR NOW FIVE???)

Date: Mon, 23 Jun 2003 12:36:59 -0500

From: "Janice M. Miller"

Reply-To: Bovine Spongiform Encephalopathy

To: BSE-L@uni-karlsruhe.de

######## Bovine Spongiform Encephalopathy #########

I am happy to provide an update on the experimental inoculation of cattle and sheep with CWD. These are ongoing experiments and updates are normally provided via presentations at meetings. Dr. Hamir has prepared a poster of the following information that will be displayed at 4 upcoming meetings this summer and fall.

Experimental Transmission of Chronic Wasting Disease (CWD) to Cattle and Sheep Progress report - June 23, 2003

Experimental Transmission to Cattle

Background:

In 1997, 13 calves were inoculated intracerebrally with brain suspension from mule deer naturally affected with CWD. During the first 3 years, 3 animals were euthanized 23, 24, and 28 months after inoculation because of weight loss (2) or sudden death (1). Although microscopic examination of the brains did not show classical lesions of transmissible spongiform encephalopathy (TSE), a specific TSE marker protein, PrPres, was detected by immunohistochemistry (IHC) and western blot. Detailed information on these animals has been published previously (A Hamir et al., J Vet Diagn Invest 13: 91-96, 2001).

Update:

During the 3rd, 4th and 6th years of observation, 7 additional animals have been euthanized due to a variety of health concerns (primarily chronic joint and foot problems). IHC and western blot results indicate that 2 of these animals, necropsied 59 and 63 months after inoculation, were positive for PrPres. One animal (# 1746) had not been eating well for approximately 1 week prior to being found recumbent. At necropsy, significant gross lesions consisted of an oblique fracture of L1 vertebral arch with extension into the body, and moderate multifocal hemorrhagic ulceration in the abomasum. Microscopic examination of brain revealed a few isolated neurons with single or multiple vacuoles, but neither neuronal degeneration nor gliosis was observed. IHC revealed the presence of PrPres in sections from several areas of the brain. The other PrPres positive animal (#1742) was euthanized after being found in lateral recumbency with a body temperature of 104.6 F. It had not shown prior clinical signs except for some decreased appetite for 2 days. Necropsy revealed only moderate hepatitis and a small renal infarct due to intravascular thrombosis.

Summary of findings on all necropsied animals to date:

Ear tag Date of Survival Disease Clinical

Histo- IHC WB

no. necropsy period course signs

pathology

__________________________________________________

1745 8/18/99 23m 2m + ± + + 1768 9/22/99 24m 3m + ± + + 1744 1/29/00 28m 3d ± - + + 1749 5/20/01 44m NA - - - - 1748 6/27/01 45m NA - - - - 1743 8/21/02 59m NA - - - - 1741 8/22/02 59m NA - - - - 1746 8/27/02 59m 7d ± ± + + 1765 11/27/02 62m 1d ± ± - - 1742 12/28/02 63m 2d ± - + +

NT = not tested; IHC = immunohistochemistry for PrPres; SAF = scrapie associated fibrils; NA = not applicable; WB = Western blot (Prionics-Check); + = lesions or antigen present; - = lesions or antigen absent; ± = signs/lesions equivocal; i/c = intracerebral; m = months; d = days.

Summary:

After 5.75 years of observation we have 5 CWD transmissions to cattle from a group of 13 inoculates. These animals, which were necropsied 23, 24, 28, 59, and 63 months after inoculation, did not show the clinical signs or histopathologic lesions typical of a TSE, but PrPres was detected in brain samples by both immunohistochemistry and western blot.

Five other animals necropsied during the 4th, 5th and 6th years of observation have not shown evidence of PrPres and the remaining 3 cattle are apparently healthy. Note that this study involved direct intracerebral inoculation of cattle with the CWD agent, which is an unnatural route of exposure. Likely, it would be more difficult to infect cattle by the oral route. Cattle have been inoculated orally at the University of Wyoming with the same inoculum used in this experiment, and 5.75 years into the study the animals remain healthy (personal communication, Dr. Beth Williams).

Experimental Transmission of CWD to sheep

Eight Suffolk sheep from the NADC scrapie-free flock were inoculated intracerebrally with the CWD brain suspension used to inoculate cattle. PRNP genotyping showed that 4 of the sheep were QQ at codon 171 and the other four were QR. Two of the QQ sheep were euthanized during the 3rd year of observation. At necropsy one of these animals had a urethral obstruction and PrPres was not detected in brain or lymphoid tissues. The other sheep, necropsied 35 months after inoculation, showed clinical signs and histopathologic lesions that were indistinguishable from scrapie. IHC tests showed typical PrPres accumulations in brain, tonsil, and some lymph nodes. The 2 remaining QQ sheep and all 4 QR sheep are apparently healthy 47 months after inoculation.

Summary:

After 4 years of observation we have 1 transmission of CWD to a 171 QQ sheep. This animal, which was necropsied 35 months after inoculation, showed clinical signs and histopathologic lesions that were indistinguishable from scrapie. Another QQ sheep that was necropsied during the 3rd year showed no evidence of prion disease and all remaining sheep (2 QQ and 4 QR) are apparently healthy.


########### http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html ############



-------- Original Message --------


Subject: Re: CWD TO CATTLE by inoculation (ok, is it three or four OR NOW FIVE???)

Date: Mon, 23 Jun 2003 09:25:27 -0500

From: "Terry S. Singeltary Sr."

Reply-To: Bovine Spongiform Encephalopathy

To: BSE-L@uni-karlsruhe.de


######## Bovine Spongiform Encephalopathy #########


Greetings List Members,

i hear now that a 5th cow has gone done with CWD from the studies of Amir Hamir et al. will Dr. Miller please confirm or deny this please, and possibly explain why this has not made the news, if in fact this is the case?

seems these cows infected with CWD/TSE did not display the usual BSE symptoms. i wonder how many more are out there in the field? course, we will never know unless someone starts rapid TSE/BSE testing in sufficient numbers to find...

thank you, kind regards, terry

Date: Sat, 23 Nov 2002 18:54:49 -0600

Reply-To: BSE

Sender: BSE

From: "Terry S. Singeltary Sr."

Subject: CWD TO CATTLE by inoculation (ok, is it three or four???)

1: J Vet Diagn Invest 2001 Jan;13(1):91-6

Preliminary findings on the experimental transmission of chronic wasting disease agent of mule deer to cattle.

Hamir AN, Cutlip RC, Miller JM, Williams ES, Stack MJ, Miller MW, O'Rourke KI, Chaplin MJ.

National Animal Disease Center, ARS, USDA, Ames, IA 50010, USA.

To determine the transmissibility of chronic wasting disease (CWD) to cattle and to provide information about clinical course, lesions, and suitability of currently used diagnostic procedures for detection of CWD in cattle, 13 calves were inoculated intracerebrally with brain suspension from mule deer naturally affected with CWD. Between 24 and 27 months postinoculation, 3 animals became recumbent and were euthanized.

Gross necropsies revealed emaciation in 2 animals and a large pulmonary abscess in the third. Brains were examined for protease-resistant prion protein (PrP(res)) by immunohistochemistry and Western blotting and for scrapie-associated fibrils (SAFs) by negative-stain electron microscopy. Microscopic lesions in the brain were subtle in 2 animals and absent in the third case. However, all 3 animals were positive for PrP(res) by immunohistochemistry and Western blot, and SAFs were detected in 2 of the animals. An uninoculated control animal euthanized during the same period did not have PrP(res) in its brain. These are preliminary observations from a currently in-progress experiment. Three years after the CWD challenge, the 10 remaining inoculated cattle are alive and apparently healthy. These preliminary findings demonstrate that diagnostic techniques currently used for bovine spongiform encephalopathy (BSE) surveillance would also detect CWD in cattle should it occur naturally.

http://www.ncbi.nlm.nih.gov/entrez/


Sat, Nov 23, 2002

Scientists unsure if CWD can jump species

By Jessica Bock Wausau Daily Herald jbock@wdhprint.com

snip...

Janice Miller, a veterinarian in charge of the experiment, said she believes previous research shows it is hard for the disease to be transmitted naturally from whitetail deer to dairy cattle. "Our study says nothing of how it could be transmitted in natural surroundings," she said.

Miller has been studying the transmission of CWD from mule deer to cattle since 1997. Since then, chronic wasting disease was transmitted to four out of 13 cattle injected with brain tissue from naturally infected mule deer, she said.

In Wyoming, Williams has been studying cattle that were given a concoction of diseased brain tissue orally, and five years into the study the animals remain healthy, Miller said. No one knows if chronic wasting disease could ever spread to another species through natural surroundings.

"Our experience is that it's pretty hard to predict," Miller said.

http://www.wausaudailyherald.com/



greetings list,

Since then, chronic wasting disease was

transmitted to four out of 13 cattle

is this a typo by the media or has another cow gone down with CWD since the preliminary findings were found?

TSS

########### http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html ############







Title: Susceptibility of cattle to first-passage intracerebral inoculation with chronic wasting disease agent from white-tailed deer

Authors

Hamir, Amirali Miller, Janice - ARS RETIRED Kunkle, Robert Hall, S - USDA, APHIS, NVSL, PL Richt, Juergen

Submitted to: Veterinary Pathology Publication Type: Peer Reviewed Journal Publication

Acceptance Date: February 20, 2007

Publication Date: July 1, 2007

Citation: Hamir, A.N., Miller, J.M., Kunkle, R.A., Hall, S.M., Richt, J.A. 2007.

Susceptibility of cattle to first-passage intracerebral inoculation with chronic wasting disease agent from white-tailed deer.

Veterinary Pathology. 44:487-493.

Interpretive Summary: This study reports findings assessing susceptibility of cattle to infection following direct surgical inoculation of the transmissible spongiform encephalopathy (TSE), chronic wasting disease (CWD, from white tailed deer) into the brain of 14 cattle. Three-month-old calves were inoculated with the CWD agent from white tailed deer. Two non-inoculated calves served as controls. Within 26 months post inoculation, 12 inoculated animals had lost weight, revealed abnormal clinical signs, and were euthanatized. Laboratory tests revealed the presence of a unique pattern of the disease agent in tissues of these animals. These findings demonstrate that when CWD is directly inoculated into the brain of cattle, 86% of inoculated cattle develop clinical signs of the disease. The findings also indicate that diagnostic techniques currently used for detection of bovine spongiform encephalopathy (BSE) would detect CWD in cattle should it ever cross the species barrier. Moreover, these findings confirm our earlier findings with CWD from mule deer, thus demonstrating a unique pattern of the CWD disease agent from deer when experimentally inoculated into cattle, further validating our ability to distinguish this form of cross-species TSE transmission from BSE in cattle.


Technical Abstract: To compare clinicopathological findings of chronic wasting disease (CWD) from white-tailed deer (CWD**wtd) with other transmissible spongiform encephalopathies [transmissible spongiform encephalopathy (TSE), prion diseases) that have been shown to be experimentally transmissible to cattle [sheep scrapie, CWD of mule deer (CWD**md) and transmissible mink encephalopathy (TME)], 14 three-month-old calves were intracerebrally inoculated with the CWD**wtd agent. Two uninoculated calves served as controls. Within 26 months post inoculation (MPI), 12 inoculated animals had lost considerable weight and eventually became recumbent. Eleven of these had clinical signs of central nervous system (CNS) abnormality and all 12 were euthanized. Although microscopic lesions of spongiform encephalopathy (SE) were not seen in CNS tissues, PrP**res was detected by immunohistochemistry (IHC) and Western blot (WB). These findings demonstrate that when CWD**wtd is intracerebrally inoculated in cattle, 86% of inoculated cattle develop abnormal clinical signs and amplify PrP**res in their CNS tissues without evidence of morphologic lesions of SE. The latter has also been shown with other TSE agents (scrapie and CWD**md) similarly inoculated into cattle. These findings suggest that the diagnostic techniques currently used for confirmation of bovine spongiform encephalopathy (BSE) would detect CWD**wtd in cattle should it occur naturally. The absence of microscopic morphologic lesions and a unique IHC pattern of CWD**wtd in cattle, suggests that it should be possible to distinguish this form of cross-species transmission from BSE in cattle.



http://www.ars.usda.gov/research/publications/publications.htm?seq_no_115=194089




TSS





***

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


http://betaamyloidcjd.blogspot.com/2010/12/alimentary-prion-infections-touch-down.html



BSE101/1 0136

IN CONFIDENCE

CMO

From: Dr J S Metters DCMO

4 November 1992

TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES

http://collections.europarchive.org/tna/20081106170650/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf



CJD1/9 0185

Ref: 1M51A

IN STRICT CONFIDENCE

From: Dr. A Wight

Date: 5 January 1993

Copies:

Dr Metters

Dr Skinner

Dr Pickles

Dr Morris

Mr Murray

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf



Friday, September 3, 2010

Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE


http://betaamyloidcjd.blogspot.com/2010/09/alzheimers-autism-amyotrophic-lateral.html



http://betaamyloidcjd.blogspot.com/



2010 PRION UPDATE

Thursday, August 12, 2010

Seven main threats for the future linked to prions


http://prionpathy.blogspot.com/2010/08/seven-main-threats-for-future-linked-to.html



http://prionpathy.blogspot.com/




Friday, October 22, 2010

Peripherally Applied Aß-Containing Inoculates Induce Cerebral ß-Amyloidosis


http://betaamyloidcjd.blogspot.com/2010/10/peripherally-applied-containing.html



Saturday, March 22, 2008

10 Million Baby Boomers to have Alzheimer's in the coming decades


http://betaamyloidcjd.blogspot.com/2008/03/10-million-baby-boomers-to-have.html



see full text Alzheimer's and CJD i.e. TSE, aka mad cow disease


http://betaamyloidcjd.blogspot.com/



Wednesday, December 29, 2010

TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY PRION END OF YEAR REPORT DECEMBER 29, 2010


http://transmissiblespongiformencephalopathy.blogspot.com/2010/12/transmissible-spongiform-encephalopathy.html



Wednesday, December 29, 2010

CWD Update 99 December 13, 2010


http://chronic-wasting-disease.blogspot.com/2010/12/cwd-update-99-december-13-2010.html




TSS

Involvement of Dab1 in APP processing and ß-amyloid deposition in sporadic Creutzfeldt–Jakob patients

Copyright © 2009 Published by Elsevier Inc.

Involvement of Dab1 in APP processing and ß-amyloid deposition in sporadic Creutzfeldt–Jakob patients

References and further reading may be available for this article. To view references and further reading you must purchase this article.

R. Gavína, c, I. Ferrerb, c, , and J.A. del Ríoa, c, ,

aMolecular and Cellular Neurobiotechnology, Institute of Bioengineering of Catalonia and Department of Cell Biology, University of Barcelona, Baldiri Reixac 15-21, 08028 Barcelona, Spain

bInstitute of Neuropathology (INP), IDIBELL-Hospital Universitari de Bellvitge, Faculty of Medicine, University of Barcelona, 08907 Hospitalet de LLobregat, Barcelona, Spain

cCentro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain

Received 27 March 2009; revised 5 October 2009; accepted 10 October 2009. Available online 21 October 2009.

Abstract Alzheimer's disease and prion pathologies (e.g., Creutzfeldt–Jakob disease (CJD)) display profound neural lesions associated with aberrant protein processing and extracellular amyloid deposits. Dab1 has been implicated in the regulation of amyloid precursor protein (APP), but a direct link between human prion diseases and Dab1/APP interactions has not been published. Here we examined this putative relationship in 17 cases of sporadic CJD (sCJD) post-mortem. Biochemical analyses of brain tissue revealed two groups, which also correlated with PrPsc types 1 and 2. One group with PrPsc type 1 showed increased Dab1 phosphorylation and lower ßCTF production with an absence of Aß deposition. The second sCJD group, which carried PrPsc type 2, showed lower levels of Dab1 phosphorylation and ßCTF production, and Aß deposition. Thus, the present observations suggest a correlation between Dab1 phosphorylation, Aß deposition and PrPsc type in sCJD.

Keywords: Prionopathies; Amyloid plaques; Alzheimer's disease; Dab1

Article Outline Introduction Patients and methods Cases PrP typing Codon 129 genotyping Immunoprecipitation and Western immunoblotting Densitometry and statistical processing Results Analysis of Dab1 phosphorylation revealed two groups of sCJD cases ßCTF production and Aß deposition in sCJD Correlation between codon 129 polymorphism with PrPsc type and Aß deposits in sCJD groups Discussion Acknowledgements References

Fig. 1. Patterns of PrPsc type 1 and type 2 (PK: proteinase K pre-treatment). Three examples of PrPsc processing are illustrated. Every sample is run in parallel with a negative control (lane 1), a typical case of PrPsc type 1 (lane 2), a typical case type 2 (lane 3) and the case problem (lane 4).

View Within Article

--------------------------------------------------------------------------------

Fig. 2. Example of Western blot determination of pDab1 (A and B) and total Dab1 protein levels (C and D) in sCJD cases. sCJD cases were categorized as described above. Protein samples from different groups of sCJD (first and second groups) are shown. (B) The densitometric results are shown. Each data item corresponding to a sCJD case is displayed in the histograms. In addition, the mean and SEM in each group is also shown. A significant increase in the pDab1/Dab1 ratio is observed in the first group of sCJD cases compared to the second sCJD group and controls. (C and D) Parallel determination of total Dab1 levels in the same sCJD protein samples. The increased phosphorylation of Dab1 in the first sCJD cases correlates with decreased levels of total protein. Each dot corresponds to a single case. Asterisks indicate significant differences between sCJD groups and controls in (B) and (D). p < 0.05; p < 0.01 (ANOVA test). View Within Article --------------------------------------------------------------------------------

Fig. 3. Example of Western blotting determination of ßCTF (A and B) in sCJD cases compared to controls. sCJD cases were categorized as described above. Decreased levels of ßCTF can be seen in the first sCJD group compared to controls. (B) Histograms showing the densitometric study as in Fig. 2. Each dot corresponds to a single case. Asterisks indicate significant differences between sCJD groups and controls. p < 0.05 (ANOVA test). View Within Article --------------------------------------------------------------------------------

Fig. 4. Double-Y graphs illustrating the densitometric results of pDab1/Dab1 ratio (left Y axis) and CTFß levels (blue right Y axis) for each case (X axis). Each dot/square corresponds to a single case. Values of pDab1/Dab1 (black squares) and CTFß (blue circles) have been linked with a line and the area (grey for pDab1/Dab1 and violet for CTFß) has been completed for each patient group. Notice the clear differences in the distribution of the grey and violet areas between the 1st and the 2nd group of sCJD cases and controls. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) View Within Article --------------------------------------------------------------------------------

Fig. 5. Low power photomicrographs illustrating examples of amyloid plaques in some of the sCJD cases used in the present study after Aß immunocytochemistry. (A) No plaques (score 0). (B) A few diffuse plaques (score +). (C) Many diffuse plaques, some neuritic plaques (score ++). See Results for details. Scale bar (A) = 500 µm pertains to (B) and (C). View Within Article --------------------------------------------------------------------------------

Table 1. Main clinical characteristics of sCJD and control cases in the present study. F: female; M: male; M: methionine; V: valine; PrP type: PrPsc type 1: lower band of glycosylated PrPsc of 21 kDa; type 2: lower band of glycosylated PrPsc of 10 kDa. Aß plaques: 0, no plaques; +, a few diffuse plaques; ++, many diffuse plaques and some neuritic plaques. View Within Article Corresponding authors. J.A. del Río is to be contacted at MCN lab Institute of Bioengineering of Catalonia Baldiri and Reixac 15-20, 08028 Barcelona, Spain. Fax: +34 934020183. I. Ferrer, Institut de Neuropatologia Servei Anatomia Patològica IDIBELL-Hospital Universitari de Bellvitge Facultat de Medicina Universitat de Barcelona Feixa LLarga sn, 08907 Hospitalet de LLobregat, Barcelona, Spain. Fax: +34 934035810.


http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WNK-4XH5MGD-1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=77549367eefa411de83e198f26401bcc


TSS


----- Original Message -----


From: "Terry S. Singeltary Sr."
To:
Sent: Monday, October 12, 2009 9:47 AM
Subject: [BSE-L] SEAC Science and Technology Committee's investigation of research funding priorities on behalf of the Advisory Committee on Dangerous Pathogens Transmissible Spongiform Encephalopathy

-------------------- BSE-L@LISTS.AEGEE.ORG --------------------

snip...


. More specific examples of unanswered questions with health implications are:

. Will the eventual elimination of classical scrapie in the EU leave an ecological niche for other TSEs such as BSE or atypical scrapie?

. Is CWD transmissible to humans?

. Can a reliable ante mortem diagnostic blood test for vCJD be developed?

. What is the true prevalence of v CJD infection (as opposed to overt disease) in the UK?


XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX

--------------------------------------------------------------------------------

. Are some commoner types of neurodegenerative disease (including Alzheimer's disease and Parkinson's disease) also transmissible? Some recent scientific research has suggested this possibility

--------------------------------------------------------------------------------

XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX


. Could cases of protease sensitive prionopathy (PSP) be missed by conventional tests which, in all other TSEs, rely on the resistance of the prion protein in the nervous system that accompanies disease to digestion by protease enzymes?

. Can we develop reliable methods for removing and detecting protein on re-usable surgical instruments?

SNIP...

FULL TEXT ;


Monday, October 12, 2009

SEAC Science and Technology Committee's investigation of research funding priorities on behalf of the Advisory Committee on Dangerous Pathogens TSE 8 October 2009


http://bse-atypical.blogspot.com/2009/10/seac-science-and-technology-committees.html




----- Original Message -----
From: "Terry S. Singeltary Sr."
To:
Sent: Monday, June 29, 2009 2:08 PM
Subject: [BSE-L] Beyond the prion principle

-------------------- BSE-L@LISTS.AEGEE.ORG --------------------



News and Views Nature 459, 924-925 (18 June 2009) doi:10.1038/459924a; Published online 17 June 2009

CELL BIOLOGY

Beyond the prion principle

Adriano Aguzzi

It seems that many misfolded proteins can act like prions - spreading disease by imparting their misshapen structure to normal cellular counterparts. But how common are bona fide prions really?

The protein-only hypothesis of prion propagation is steadily gaining ground. First envisaged by John Stanley Griffith1 and later formalized by Stanley Prusiner2, this theory proposes the existence of an infectious agent composed solely of protein. Three reports, two in Nature Cell Biology3,4 and one in The Journal of Cell Biology5, now contend that, far from being confined to the rare prion diseases, prion-like transmission of altered proteins may occur in several human diseases of the brain and other organs.

Prions are now accepted as causing the transmissible spongiform encephalopathies, which include scrapie in sheep, bovine spongiform encephalopathy (BSE, or mad cow disease) and its human variant Creutzfeldt-Jakob disease. The infectious prion particle is made up of PrPSc, a misfolded and aggregated version of a normal protein known as PrPC. Like the growth of crystals, PrPSc propagates by recruiting monomeric PrPC into its aggregates - a process that has been replicated in vitro6 and in transgenic mice7. The breakage of PrPSc aggregates represents the actual replicative event, as it multiplies the number of active seeds8.

Apart from prion diseases, the misfolding and aggregation of proteins into various harmful forms, which are collectively known as amyloid, causes a range of diseases of the nervous system and other organs. The clinical characteristics of amyloidoses, however, gave little reason to suspect a relationship to prion diseases. Hints of prion-like behaviour in amyloid have emerged from studies of Alzheimer's disease and Parkinson's disease. Alzheimer's disease had been suspected to be transmissible for some time: an early report9 of disease transmission to hamsters through white blood cells from people with Alzheimer's disease caused great consternation, but was never reproduced. Much more tantalizing evidence came from the discovery10,11 that aggregates of the amyloid-â (Aâ) peptide found in the brain of people with Alzheimer's disease could be transmitted to the brain of mice engineered to produce large amounts of the Aâ precursor protein APP. Another study12 has shown that healthy tissue grafted into the brain of people with Parkinson's disease acquires intracellular Lewy bodies - aggregates of the Parkinson's disease-associated protein á-synuclein. This suggests prion-like transmission of diseased protein from the recipient's brain to the grafted cells.

These findings10-12 raise a provocative question. If protein aggregation depends on the introduction of 'seeds' and on the availability of the monomeric precursor, and if, as has been suggested13, amyloid represents the primordial state of all proteins, wouldn't all proteins - under appropriate conditions - behave like prions in the presence of sufficient precursor? Acceptance of this concept is gaining momentum. For one thing, an increasing wealth of traits is being found in yeast, fungi and bacteria that can best be explained as prion-like phenomena (see table). And now, Ren and colleagues3 provide evidence for prion-like spread of polyglutamine (polyQ)- containing protein aggregates, which are similar to the aggregates found in Huntington's disease. They show that polyQ aggregates can be taken up from the outside by mammalian cells. Once in the cytosol, the polyQ aggregates can grow by recruiting endogenous polyQ. Clavaguera et al.4 report similar findings in a mouse model of tauopathy, a neurodegenerative disease caused by intraneuronal aggregation of the microtubule-associated tau protein. Injection of mutant human tau into the brain of mice overexpressing normal human tau transmitted tauopathy, with intracellular aggregation of previously normal tau and spread of aggregates to neighbouring regions of the brain. Notably, full-blown tauopathy was not induced in mice that did not express human tau. Assuming that tau pathology wasn't elicited by some indirect pathway (some mice overexpressing mutated human tau develop protein tangles even when exposed to un related amyloid aggregates14), this sequence of events is reminiscent of prions. Finally, Frost and colleagues5 show that extracellular tau aggregates can be taken up by cells in culture. Hence, tau can attack and penetrate cells from the outside, sporting predatory behaviour akin to that of prions.

Yet there is one crucial difference between actual prion diseases and diseases caused by other prion-like proteins (let's call them prionoids) described so far (see table). The behaviour of prions is entirely comparable to that of any other infectious agent: for instance, prions are transmissible between individuals and often across species, and can be assayed with classic microbiological techniques, including titration by bioassay. Accordingly, prion diseases were long thought to be caused by viruses, and BSE created a worldwide panic similar to that currently being provoked by influenza. By contrast, although prionoids can 'infect' neighbouring molecules and sometimes even neighbouring cells, they do not spread within communities or cause epidemics such as those seen with BSE.

So, should any amyloid deserve an upgrade to a bone fide prion status? Currently, amyloid A (AA) amyloidosis may be the most promising candidate for a truly infectious disease caused by a self-propagating protein other than PrPSc. AA amyloid consists of orderly aggregated fragments of the SAA protein, and its deposition damages many organs of the body. Seeds of AA amyloid can be excreted in faeces15, and can induce amyloidosis if taken up orally (at least in geese)16. Also, AA amyloid may be transmitted between mice by transfusion of white blood cells17. So, like entero viruses and, perhaps, sheep scrapie prions, AA amyloid seems to display all the elements of a complete infectious life cycle, including uptake, replication and release from its host.

There are intriguing evolutionary implications to the above findings. If prionoids are ubiquitous, why didn't evolution erect barriers to their pervasiveness? Maybe it is because the molecular transmissibility of aggregated states can sometimes be useful. Indeed, aggregation of the Sup35 protein, which leads to a prion-like phenomenon in yeast, may promote evolutionary adaptation by allowing yeast cells to temporarily activate DNA sequences that are normally untranslated18. Mammals have developed receptors for aggregates, and ironically PrPC may be one of them19, although these receptors have not been reported to mediate protective functions. Therefore, we shouldn't be shocked if instances of beneficial prionoids emerge in mammals as well. ¦

Adriano Aguzzi is at the Institute of Neuropathology, University Hospital of Zurich, CH-8091 Zurich, Switzerland. e-mail: adriano.aguzzi@usz.ch

1. Griffith, J. S. Nature 215, 1043-1044 (1967). 2. Prusiner, S. B. Science 216, 136-144 (1982). 3. Ren, P.-H. et al. Nature Cell Biol. 11, 219-225 (2009). 4. Clavaguera, F. et al. Nature Cell Biol. doi:10.1038/ncb1901 (2009). 5. Frost, B., Jacks, R. L. & Diamond, M. I. J. Biol. Chem. 284, 12845-12852 (2009). 6. Castilla, J., Saá, P., Hetz, C. & Soto, C. Cell 121, 195-206 (2005). 7. Sigurdson, C. J. et al. Proc. Natl Acad. Sci. USA 106, 304-309 (2009). 8. Aguzzi, A. & Polymenidou, M. Cell 116, 313-327 (2004). 9. Manuelidis, E. E. et al. Proc. Natl Acad. Sci. USA 85, 4898-4901 (1988). 10. Kane, M. D. et al. J. Neurosci. 20, 3606-3611 (2000). 11. Meyer-Luehmann, M. et al. Science 313, 1781-1784 (2006). 12. Li, J.-Y. et al. Nature Med. 14, 501-503 (2008). 13. Chiti, F. & Dobson, C. M. Annu. Rev. Biochem. 75, 333-366 (2006). 14. GÖtz, J., Chen, F., van Dorpe, J. & Nitsch, R. M. Science 293, 1491-1495 (2001). 15. Zhang, B. et al. Proc. Natl Acad. Sci. USA 105, 7263-7268 (2008). 16. Solomon, A. et al. Proc. Natl Acad. Sci. USA 104, 10998-11001 (2007). 17. Sponarova, J., NystrÖm, S. N. & Westermark, G. T. PLoS ONE 3, e3308 (2008). 18. True, H. L. & Lindquist, S. L. Nature 407, 477-483 (2000). 19. Laurén, J. et al. Nature 457, 1128-1132 (2009).

PRIONS AND POTENTIAL PRIONOIDS

Disease Protein Molecular transmissibility Infectious life cycle Prion diseases PrPSc Yes Yes Alzheimer's disease Amyloid-ß Yes Not shown Tauopathies Tau Yes Not shown Parkinson's disease a-Synuclein Host-to-graft Not shown AA amyloidosis Amyloid A Yes Possible Huntington's disease Polyglutamine Yes Not shown Phenotype Protein Molecular transmissibility Infectious life cycle Suppressed translational termination (yeast) Sup35 Yes Not shown Heterokaryon incompatibility (filamentous fungi) Het-s Yes Not shown Biofilm promotion (bacteria) CsgA Yes Not shown In humans and animals, infectious prion diseases are caused by PrPSc, which spreads by recruiting its monomeric precursor PrPC into aggregates. Aggregates then multiply by breakage, a process that is termed molecular transmissibility. Other proteins involved in disease and in phenotypes of fungi and bacteria, can also undergo self-sustaining aggregation, but none of these 'prionoid' proteins behaves like typical infectious agents, nor do any of them enact a complete infectious life cycle - with the possible exception of AA amyloid. Correction In the News & Views article "Immunology: Immunity's ancient arms" by Gary W. Litman and John P. Cannon (Nature 459, 784-786; 2009), the name of the fi rst author of the Nature paper under discussion was misspelt. The author's name is P. Guo, not Gou as published.

© 2009 Macmillan Publishers Limited. All rights reserved

http://www.nature.com/nature/journal/v459/n7249/full/459924a.html




Thursday, February 26, 2009

'Harmless' prion protein linked to Alzheimer's disease Non-infectious form of prion protein could cause brain degeneration ???

http://betaamyloidcjd.blogspot.com/2009/02/harmless-prion-protein-linked-to.html




IN STRICT CONFIDENCE

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf




CJD1/9 0185

Ref: 1M51A

IN STRICT CONFIDENCE

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 neurodegeneradve 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.

93/01.05/4.1tss

http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf




Regarding Alzheimer's disease

(note the substantial increase on a yearly basis)

http://www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf




snip...

The pathogenesis of these diseases was compared to Alzheimer's disease at a molecular level...

snip...

http://www.bseinquiry.gov.uk/files/yb/1990/03/12003001.pdf




And NONE of this is relevant to BSE?

There is also the matter whether the spectrum of ''prion disease'' is wider than that recognized at present.

http://www.bseinquiry.gov.uk/files/yb/1990/07/06005001.pdf




THE LINE TO TAKE.

http://www.bseinquiry.gov.uk/files/yb/1990/07/09001001.pdf




BSE101/1 0136

IN CONFIDENCE

5 NOV 1992

CMO From: Dr J S Metters DCMO 4 November 1992

TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES

http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf




also, see the increase of Alzheimer's from 1981 to 1986

http://www.bseinquiry.gov.uk/files/yb/1988/07/08014001.pdf




Occasional PrP plaques are seen in cases of Alzheimer's Disease

snip...

full text;

http://www.bseinquiry.gov.uk/files/ws/s310.pdf




Tuesday, August 26, 2008

Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3

http://betaamyloidcjd.blogspot.com/2008/08/alzheimers-transmission-of-aa.html




see full text ;

http://betaamyloidcjd.blogspot.com/2009/02/harmless-prion-protein-linked-to.html




Alzheimer's and CJD

http://betaamyloidcjd.blogspot.com/




MAD COW DISEASE, AND U.S. BEEF TRADE

MAD COW DISEASE, CJD, TSE, SOUND SCIENCE, COMMERCE, AND SELLING YOUR SOUL TO THE DEVIL


http://usdameatexport.blogspot.com/2009/10/mad-cow-disease-and-us-beef-trade.html





Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA