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

The Transcellular Spread of Cytosolic Amyloids, Prions, and Prionoids

Neuron

Perspective

The Transcellular Spread of Cytosolic Amyloids, Prions, and Prionoids

Adriano Aguzzi1,* and Lawrence Rajendran2,* 1Institute of Neuropathology, University Hospital of Zu¨ rich, Schmelzbergstrasse 12, CH-8091 Zu¨ rich, Switzerland 2Systems and Cell Biology of Neurodegeneration, Psychiatry Research, University of Zurich, CH-8008 Zu¨ rich, Switzerland *Correspondence: adriano.aguzzi@usz.ch (A.A.), rajendran@bli.uzh.ch (L.R.) DOI 10.1016/j.neuron.2009.12.016

Recent reports indicate that a growing number of intracellular proteins are not only prone to pathological aggregation but can also be released and ‘‘infect’’ neighboring cells. Therefore, many complex diseases may obey a simple model of propagation where the penetration of seeds into hosts determines spatial spread and disease progression. We term these proteins prionoids, as they appear to infect their neighbors just like prions—but how can bulky protein aggregates be released from cells and how do they access other cells? The widespread existence of such prionoids raises unexpected issues that question our understanding of basic cell biology.

Imagine that you are a neuroscientist vacationing on Mars. One day you encounter a colony of Martians that, as it happens, look similar to water bottles. The Martians are highly distressed and seek your advice, as their community is plagued by an enigmatic transmissible disease. Intrigued, you agree to help. It turns out that the bodies of your exobiotic friends consist of bottles filled with a supersaturated salt solution. At some point crystals have started forming in one individual, and then crystallization has somehow been transferred to other community members. Lacking molecular insight, you would initially conclude that the Martians are affected by an infectious agent. Through ingenuity and technology, you may then discover that the infectious agent is exceedingly simple and homogeneous, that it lacks informational nucleic acids, and that it is generated both by ordered aggregation of an intrinsic precursor and by appositional growth of extrinsically added seeds. Your discovery will earn you the Intergalactic Nobel Prize, yet two crucial questions remain unanswered: how do the crystals transfer between individuals, and what can be done to prevent this from happening?

Middle-aged readers may feel reminded of the plot for Andromeda Strain, a stunningly prescient novel published in 1969 by the late Michael Crichton. But the sci-fi scenario described above is also the blueprint of Prusiner’s hypothesis of prion propagation. Over time, we have learned that prions consist of PrPSc, higher-order aggregates of a physiological protein termed PrPC. Accordingly, prions propagate through elongation and breakage of PrPSc aggregates (Aguzzi and Polymenidou, 2004)—not unlike the crystals vexing our extraterrestrial friends.

There is mounting evidence (Clavaguera et al., 2009; Frost et al., 2009; Ren et al., 2009; Desplats et al., 2009; Luk et al., 2009) suggesting that the events sketched above, far from being confined to science-fiction and prion diseases (whose incidence in humans is just z1/106/year), may underlie highly prevalent human diseases of the brain and many other organs. The unifying characteristics of all these diseases is the aggregation of proteins into highly ordered stacks, henceforth termed ‘‘amyloids’’ irrespective of their size. Since PrPSc undoubtedly fulfills the latter definition of amyloid, one is led to wonder whether the prion principle may be much more pervasive than previously appreciated and whether many more diseases of unknown cause may eventually turn out to rely on prion-like propagation (Table 1, upper panel). Even more intriguingly, a number of proteins appear to exert normal functions when arranged in highly ordered stacks that are similar to amyloids and to prionoids (Table 1, lower panel).

Prions and Prionoids

There is one crucial difference between bona fide prion diseases and all other amyloids and prion-like phenomena hitherto described in uni- and pluricellular organisms (Table 1). Prions are infectious agents, transmissible between individuals, and tractable with microbiological techniques—including, e.g., titer determinations. Even if certain amyloids of yeast and mammals appear to infect neighboring molecules and sometimes neighboring cells, they do not propagate within communities, and none of them were found to cause macroepidemics such as Kuru and bovine spongiform encephalopathy. We have therefore termed these self-aggregating proteins ‘‘prionoids’’ (Aguzzi, 2009), since the lack of microbiological transmissibility precludes their classification as true prions.

Some prionoids may soon qualify for an upgrade to prion status. At least in select settings, amyloid A (AA) amyloidosis may exist as a truly infectious disease based on a self-propagating protein. AA amyloid consists of orderly aggregated fragments of SAA protein, whose deposition can damage many organs of the body. Somewhat bizarrely, AA aggregation is also present in the liver of force-fed geese, hence contributing to the pathophysiology of foie gras (Solomon et al., 2007). AA seeds can induce amyloidosis upon transfer of white blood cells (Sponarova et al., 2008). Furthermore, AA seeds are excreted with the feces, and AA amyloidosis is endemic in populations of cheetah (Zhang et al., 2008). It is therefore tantalizing to suspect that amyloid may entertain the complete life cycle of an infectious agent, including transmission by the orofecal and hematogenous route—similarly to enteroviruses and, perhaps, scrapie prions. While there may be many other good reasons to avoid foie gras, including, e.g., animal welfare concerns, gourmets may not need to panic: under experimental conditions, AA amyloidosis is only transmitted to AgNO3-pretreated mice that display elevated levels of the SAA precursor protein.

Alzheimer’s disease (AD) has long been suspected to be a transmissible disease, but these suspicions have never materialized in epidemiological studies. On the other hand, Mathias Jucker and Lary Walker observed that injection of the Ab peptide from human AD brains induced robust and convincing aggregation of Ab in transgenic mice overexpressing the Ab precursor protein, APP (Kane et al., 2000; Meyer-Luehmann et al., 2006). Jucker’s finding raises an epistemologically significant question: if aggregation depends on the introduction of seeds and on the availability of the monomeric precursor, and if amyloid represents the primordial state of all proteins (Chiti and Dobson, 2006), wouldn’t all proteins—under appropriate conditions— give rise to prionoids in the presence of sufficient precursor?

The issues sketched above go well beyond AD and prions. There are many other diseases—not necessarily involving the nervous system—whose pathogenesis involves ordered aggregation of proteins, but for which there is no evidence of transmission between individuals. The best-studied of these are the systemic amyloidoses, which come about through the nucleation of some aggregation-prone proteins such as transthyretin and immunoglobulin light chains. Yet ordered protein aggregation is by no means confined to the ‘‘classical’’ amyloidoses and extends to a number of conditions, some of which have been rather unexpected.

Type II diabetes is yet another disease whose pathogenesis may involve ordered protein aggregation. Evidence to support this idea was discovered over a century ago (Opie, 1901) but was largely forgotten until recently. It is now evident that aggregation of islet amyloid polypeptide (IAPP) is an exceedingly frequent feature of type II diabetes. IAPP amyloids damage the insulin-producing b cells within pancreatic islets and may crucially contribute to the pathogenesis of diabetes (Hull et al., 2004). It is unknown, however, whether IAPP deposition simply accrues linearly with IAPP production or whether it spreads prion-like from one pancreatic islet to the next.

A body of recent work supports the idea that many aggregation proteinopathies are, in one way or another, transmissible. A recent report showed that a-synuclein is released from neurons and is then taken up by the neighboring cells, thereby aiding in a progressive spread of the protein (Desplats et al., 2009; Lee et al., 2005). When exogenously added to cultured cells, fluorescently labeled, recombinant a-synuclein was internalized from the extracellular milieu into the cytosol. Furthermore, injection of GFP-labeled mouse cortical neuronal stem cells into the hippocampus of a-synuclein-transgenic mice led to the efficient uptake of the host a-synuclein into the grafted cells after just 4 weeks. These findings are reminiscent of the observation that healthy fetal tissue, grafted into the brains of Parkinson’s disease patients, acquired intracellular Lewy bodies. The latter phenomenon is somewhat anecdotal and has been disputed (Mendez et al., 2008), yet it would be entirely compatible with the hypothesis that a-synuclein aggregates are prionoids (Li et al., 2008). A similar study conclusively demonstrated that exogenous a-synuclein fibrils induced the formation of Lewy body-like intracellular inclusions in vitro (Luk et al., 2009). This study also showed that the conversion of the host cell a-synuclein was accompanied by dramatic changes, including hyperphosphorylation and ubiquitination of a-synuclein aggregates—thus recapitulating some key features of the human pathology.

In experiments conceptually analogous to those discussed above, polyglutamine-containing protein aggregates similar to those present in Huntington’s disease and in spinocerebellar ataxias exhibited prion-like propagation (Ren et al., 2009). There, aggregation of huntingtin progressed from the extracellular space to the cytosol and eventually to the nucleus. What is more, similar phenomena occurred upon exposure of cells to Sup35 aggregates, which consist of a yeast protein for which there are no known mammalian paralogs. This suggests that the prionoid properties are intrinsic to amyloids and are not tied to the origin or function of their monomeric precursor protein.

In another work, Tolnay and colleagues report a similar phenomenon in a mouse model of ‘‘tauopathy,’’ a neurodegenerative disease due to intraneuronal aggregation of the microtubule- associated tau protein (Clavaguera et al., 2009). Aggregation- prone mutant tau, when extracted from the brain of transgenic mice, induced tauopathy in mice overexpressing wild-type tau. Assuming that tau pathology wasn’t elicited by some indirect pathway (tau-overexpressing mice develop tangles when exposed to Ab aggregates [Go¨ tz et al., 2001]), these transgenic mice appear to behave like the Martian bottles, since tauopathy was not induced in mice expressing normal levels of tau. In yet another study, the microtubule binding part of the full-length tau was found to attack and penetrate cells when added exogenously, and this again induced host tau misfolding (Frost et al., 2009). This study also showed that aggregated intracellular Tau spontaneously transferred between two cocultured cell populations (Frost et al., 2009). In the case of both tau and polyglutamines, the protein aggregates appear to gain access to the cytosol and to cause further aggregation of their host counterparts—presumably by nucleation.

The unifying characteristics of all these diseases is the aggregation of proteins into highly ordered stacks, termed amyloids irrespective of their size; the growth of these structures also exhibits generic features (Knowles et al., 2009) shared with a wide class of self-assembly phenomena characterized by elongation and fragmentation, such as the formation of analogous aggregates in micro-organisms and in vitro. Two conclusions can be drawn from the recent studies: (1) an unexpected number of amyloidogenic proteins can be released from affected cells in the form of extracellular amyloid seeds, and (2) even more surprisingly, these seeds can then re-enter other cells and nucleate the aggregation of their intracellular counterparts—in the cytosol or even in the nucleus. The biological and practical implications are far-reaching. On the one hand, cell therapies of aggregation diseases may be more difficult than anticipated, as the transplanted cells may undergo infection. A possible remedy could consist in the removal of the genes encoding the precursor of the offending proteins from the cells utilized for therapy—e.g., using the zinc-finger nuclease strategy (Hockemeyer et al., 2009). On the other hand, a novel paradigm of amyloid pathogenesis is emerging from these data, whereby each prionoid behaves as a self-assembling and self-replicating nanomachine.

Conversely, these findings raise a number of enigmas for which we are lacking any satisfactory answer. Whereas PrPC and the Ab are luminally exposed, a-synuclein and tau are cytoplasmic— and huntingtin is even nuclear. Aggregates of both Ab and PrPSc, as well as their monomeric precursors, are found in the extracellular space; it is hence intuitive that the nucleation process can propagate spatially across large distances. Instead, the propagation of cytoplasmic prionoids challenges our basic cell-biological understanding, since it posits that protein aggregates are released into the extracellular space and can subsequently reenter—and wreak havoc—in the cytosol of other cells. The release of cytosolic amyloids is supported by the amelioration of Lewy body pathology in a-synuclein transgenic mice immunized with human a-synuclein (Masliah et al., 2005). Similarly, anti-tau oligomer immunotherapy reduced brain pathology (Asuni et al., 2007), and immunization with mutant SOD1 led to clearance of SOD1 and delayed the onset of the disease in mice (Urushitani et al., 2007). All of these results indicate that cytosolic amyloids are somehow accessible to extracellular antibodies. This raises the question of how these proteins are released into the extracellular space (‘‘cytosol to lumen’’) and how they subsequently re-enter cellular cytosol (‘‘lumen to cytosol’’). Both events require trespassing lipid bilayer barriers—by no means a trivial feat for proteins, let alone highmolecular- weight aggregates.

snip...

Conclusion

The wave of these recent reports on the prion-like behavior of disparate pathogenic proteins raises many more questions than it answers. Here we have highlighted a number of open issues related to mechanisms of cell-to-cell spread of prionoids. The resolution of such issues may constitute the first step toward the development of rational strategies aimed at blocking transcellular propagation. There is justified hope that the latter may decelerate the progression of pathology and, consequently, help toward fighting the devastating outcome of aggregation proteinopathies.

http://www.cell.com/neuron/abstract/S0896-6273(09)01006-X



Sunday, July 18, 2010

Alzheimer's Assocition International Conference on Alzheimer's Disease (updated diagnostic criteria) 2010 July 10 - 15 Honolulu, Hawaii

http://betaamyloidcjd.blogspot.com/2010/07/alzheimers-assocition-international.html



Saturday, April 24, 2010

New connection between Alzheimer’s and prionic illnesses discovered

http://betaamyloidcjd.blogspot.com/2010/04/new-connection-between-alzheimers-and.html



Sunday, June 7, 2009

ALZHEIMER'S DISEASE IS TRANSMISSIBLE

http://betaamyloidcjd.blogspot.com/2009/06/alzheimers-disease-is-transmissible.html



Wednesday, April 14, 2010

Food Combination and Alzheimer Disease Risk A Protective Diet

http://betaamyloidcjd.blogspot.com/2010/04/food-combination-and-alzheimer-disease.html



Alzheimer's and CJD


http://betaamyloidcjd.blogspot.com/




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