In vitro formation of rogue prion
In situ formation of rogue prion
Friedreich's ataxia homologue found in yeast
Two new GPI neural proteins found
Familial CJD at codon 200
Mad Cow appeal: Researchers need brain and spinal-tap samples
1000 brain dementia study: half of CJD cases missed
Heynkes' annotated TSE citation database up to 4687
Proposal for prion disease nomenclature
Proc. Natl. Acad. Sci. USA free fulltext Vol. 94, pp. 4931-4936, May 13 1997 Alex Bossers, Peter B. G. M. Belt, Gregory J. Raymond, Byron Caughey, Ruth de Vries, and Mari A. SmitsExcerpts: Polymorphisms in the PrP gene are linked to differences in susceptibility for prion diseases. The mechanisms underlying these effects are still unknown. Here we describe studies of the influence of sheep PrP polymorphisms on the conversion of PrPC into protease-resistant forms. [See link for DNA and amino acid sequences of sheep alleles.]
In a cell-free system, sheep PrPSc induced the conversion of sheep PrPC into protease-resistant PrP (PrP-res) similar or identical to PrPSc. Polymorphisms present in either PrPC or PrPSc had dramatic effects on the cell-free conversion efficiencies. The PrP variant associated with a high susceptibility to scrapie and short survival times of scrapie-affected sheep was efficiently converted into PrP-res. The wild-type PrP variant associated with a neutral effect on susceptibility and intermediate survival times was converted with intermediate efficiency. The PrP variant associated with scrapie resistance and long survival times was poorly converted.
Thus the in vitro conversion characteristics of the sheep PrP variants reflect their linkage with scrapie susceptibility and survival times of scrapie-affected sheep. The modulating effect of the polymorphisms in PrPC and PrPSc on the cell-free conversion characteristics suggests that, besides the species barrier, polymorphism barriers play a significant role in the transmissibility of prion diseases.
Several PrP polymorphisms of humans have been associated with incidence, susceptibility, and pathology of the disease (1, 8). For sheep, eight mutually exclusive PrP polymorphisms have been described (9-15), resulting in nine different allelic variants. The allelic variants with polymorphisms at codons 112, 137, 141, 154, or 211 are rare and have not been significantly associated with any disease phenotype yet.
In contrast, the PrPVQ allele (polymorphic amino acids at positions 136 and 171 are indicated by superscript single-letter code) is associated with high susceptibility to scrapie and short survival times of scrapie-affected sheep (9-12, 15-18), whereas the PrPAR allele is associated with resistance or incubation times that span beyond the lifetime of sheep (9-12, 16, 17).
In breeds where PrPVQ is rare, e.g. the Suffolk breed, the wild-type PrPAQ allele is associated with susceptibility to scrapie, although with a low or incomplete penetrance (18, 19). The mechanisms by which the different PrP allelic variants contribute to differences in scrapie susceptibility and survival time are not yet understood. However, it is possible that the various PrPC variants differ in their conversion kinetics into PrPSc. Such differences may be due to differences in expression levels, in cotranslational or posttranslational modifications, and/or differences in conformational structures of the various PrP variants.
In this paper we report, for the first time to our knowledge, the cell-free conversion of sheep PrPC into protease-resistant forms similar or identical to ShPrPSc. In addition we report that polymorphisms that are associated with differences in scrapie susceptibility and differences in survival times of scrapie affected sheep also account for comparable differences in cell-free conversion efficiencies. This suggests that the PrP conversion kinetics are directly related to scrapie susceptibility and the length of survival times of sheep affected by natural scrapie.
Because there is a good correlation between in vitro cell-free conversion data and in vivo scrapie susceptibility data thus far (9-12, 16, 17), this assay may be useful for determining the relative susceptibility of individual allelic forms of PrP to different prion sources and/or the relative transmissibility of these prion sources.
The efficiency of the cell-free conversion reaction was strongly dependent on both the type of PrPC variant and on the source of PrPSc used to induce the conversion. The PrPCVQ variant, which is associated with high susceptibility and short survival times of scrapie-affected sheep, was very efficiently converted into protease-resistant forms. The wild-type PrPCAQ variant, which is associated with a neutral effect on susceptibility and intermediate survival times, was converted into protease-resistant forms with intermediate efficiency. The PrPCAR variant, which is associated with resistance and long survival times, was poorly converted into protease-resistant forms.
Although in some breeds, i.e. Suffolk and Romanov, PrPAQ is associated with an incomplete penetrance to scrapie susceptibility, probably due to the low incidence of PrPVQ (16, 19, 32), PrPVQ carriers of these breeds still have the shortest scrapie survival time (16, 32). Another point of interest is the finding that PrPCAR can be converted, although with a very low efficiency, into protease-resistant forms suggesting the possibility of scrapie agent replication in PrPAR-carrying sheep as has been described by Ikeda et al. (32).
Not only the primary PrPC sequence was found to determine the conversion characteristics but also the primary amino acid sequence of PrPSc. PrPC(VQ/VQ) converted PrPCVQ, PrPCAQ, and PrPCAR with decreasing efficiencies. In contrast, PrPSc(AQ/AQ) converted PrPCVQ almost as efficiently as the PrPCAQ variant. The PrPCAR variant was poorly converted by both PrPSc isolates. This suggests that scrapie susceptibility is not only determined by the PrP genotype of the acceptor animal but also by the PrP genotype of the animal that produced the infectious PrPSc.
This is consistent with the finding that the SSBP/1 scrapie isolate obtained from PrPVQ NPU-Cheviot sheep is best transmitted to PrPVQ sheep (12, 17). It is also consistent with the striking behavior of the CH1641 scrapie isolate, which was primarily isolated from a positive line (mainly PrPVQ-carrying) NPU-Cheviot sheep, when passaged in positive-line or negative-line (non-PrPVQ) Cheviot sheep.
The first (primary) intracerebral passage of this positive-line material to positive-line Cheviot sheep resulted in short incubation times. Passage of the primary CH1641 isolate into negative-line Cheviot sheep resulted in longer incubation times (33) probably due to polymorphism barriers. If the negative-line passaged isolates were subsequently passaged in negative-line Cheviot sheep the incubation times in this line of sheep decreased (17, 33). A subsequent passage from these negative-line to positive-line Cheviot sheep increased the incubation times dramatically (17, 33) again probably due to the polymorphism barrier.
Modification of scrapie isolate properties were also found in mice scrapie transmission experiments in which the properties of PrPSc could be modified by passage of scrapie isolates through mice with different PrPC amino acid sequences (34). Further support is derived by the transmission of human Creutzfeldt-Jakob disease or GSS to mice expressing chimeric mouse/human PrP transgenes carrying specific mutations. Mice carrying the Glu-to-Lys mutation at position 200 (E200K) were resistant to human prions from a patient with GSS carrying a Pro-to-Leu mutation at position 102 (P102L) but were susceptible to prions from familial Creutzfeldt-Jakob disease patients harboring the E200K mutation.
However, mice carrying the mouse/human transgene with the P102L mutation were susceptible to GSS prions (24). Interestingly, a homogenate of bovine spongiform encephalopathy, of which the primary amino acid sequence (at the polymorphic amino acid positions of sheep PrP) is best comparable with the sheep PrPAQ genotype, gives the shortest incubation times in PrPAQ sheep if inoculated by the intracerebral route. If inoculated via the longer oral route however, PrPVQ sheep have the shortest incubation time (17).
Probably inoculation via the oral route, compared with inoculation by the intracerebral route, extends the incubation time long enough to overcome the polymorphism barrier and subsequently allows the agent to spread more quickly using PrPCVQ instead of PrPCAQ. Preliminary data from cell-free conversion experiments with the three PrPC variants using PrPSc isolated from a PrPVQ/AQ sheep suggest that this PrPSc isolate mainly consists of PrPCVQ because this PrPSc(VQ/AQ) isolate converted PrPCVQ at least three times as efficiently as PrPCAQ into protease-resistant forms (Fig. 4).
This again is consistent with the finding that PrPCVQ is more readily converted into PrP-res than PrPCAQ. Thus in sheep containing the mutant PrPVQ allele, it is likely that the PrPCVQ variant will be the preferred converted variant, similar to what has been found for the mutant human PrP allele in GSS (35). Consequently, after infection of flocks of sheep having the PrPVQ allele, the agent pool would be predicted to become enriched for PrPVQ.
...Studies with the cell-free conversion reaction (36) and small synthetic PrP peptides (37) are consistent with a nucleated polymerization mechanism (38, 39). The conversion of PrPC to PrPSc involves a transition from a state that is predominantly -helical to one that is largely -sheet (4, 5, 40). PrPC may rapidly interchange between these two conformations in its normal monomeric state but only be stabilized and accumulated in the -sheet conformation by binding to a preformed PrPSc polymer (37, 38, 41). Alternatively, the transition to the PrPSc conformation may only be induced (catalyzed) upon direct binding of PrPC to the PrPSc polymer. PrP polymorphisms may influence the equilibrium between the -helical and -sheet conformations in PrPC and/or the ease with which PrPSc induces PrPC to switch to the -sheet conformation. Polymorphisms that destabilize the -helical conformation of PrPC would be expected to have these effects.
In this study we have tested the cell-free conversion of three (PrPVQ, PrPAQ, and PrPAR) of the nine PrP variants found in sheep, including the two allelic variants that are associated with the extremes in susceptibility to scrapie (highly susceptible or resistant). From the other six allelic variants: PrPT112AQ, PrPAT137Q, PrPAF141Q, PrPAH154Q, PrPAH, and PrPAQQ211, it is not known whether they are significantly associated with susceptibility to natural or experimental scrapie in sheep. Using the recently published high-resolution NMR structure of the mouse PrPC domain containing residues 121-232 together with Novotny secondary structure predictions, it might be possible to rationalize the effects of certain of the sheep PrP polymorphisms on PrPC conformation.
At least two other polymorphisms in the sheep PrP gene could be associated, by these predictions, with scrapie susceptibility. The PrPAT137Q variant could be grouped with the PrPVQ variant, because both give a prediction of more -sheeted structure and a change in hydrophobicity in the loop between -sheet-1 and -helix-1, which may indicate helix breaking or hydrophobic core destabilizing properties as found in theoretical studies of the Ala to Val mutation at position 117 in the human PrP sequence (42). The PrPAH154Q variant is protective against scrapie, and no scrapie-affected sheep with this genotype have been found (10, 12, 15, 32).
This variant could be grouped with the PrPAR variant, because both involve a charge inversion compared with the wild-type PrPAQ variant. The latter two polymorphisms are located in the loops between -helix-1 and -sheet-2, and between -sheet-1 and -helix-3, respectively, and may influence the stabilization of the hydrophobic core or the dipolar character of PrPC. The other four alleles did not show differences in Novotny secondary structure predictions other than the PrPAQ variant and therefore probably may be grouped with this variant. Additional cell-free conversion data with all known sheep PrPC variants may enable us in the near future to determine more exactly the relative scrapie susceptibility between sheep having different PrP alleles.
Cell May 16, 1997 Review [Full Text] Arthur L. Horwich and Jonathan S. Weissman
J Gen Virol 77 ( Pt 10): 2669-2673 (Oct 1996) Bossers A, Schreuder BE, Muileman IH, Belt PB, Smits MASeveral allelic variants of the sheep PrP gene are associated with scrapie susceptibility. However, it is not known whether, and to what extent, the PrP genotype contributes to determining survival times of scrapie sheep. We therefore determined the PrP genotype and life spans of over 50 Flemish and Swifter sheep within a single scrapie-affected flock. Eighty-three per cent of the scrapie sheep were homozygous for the PrP(VQ) allele (polymorphic amino acids at codons 136 and 171 are indicated) and these sheep died from scrapie at a mean age of 25 months.
In sheep heterozygous for PrP(VQ), development of scrapie was delayed or did not occur. Sheep with at least one PrP(AR) allele, including PrP(VQ)/PrP(AR) sheep, did not develop scrapie. No scrapie sheep were found without a PrP(VQ) allele. We conclude that the PrP genotype contributes to determining survival times of sheep with natural scrapie. Additionally, we describe two novel sheep PrP allelic variants.
10 June 1997The important May 13 PNAS article by Bossers, Caughey, et al. carefully quantitates the conversion of various sheep prion gene products to protease resistant product using infectious prion prepared from various genetic backgrounds. The assay itself involves 2-5 days of incubating substrate (various alleles ) with catalysts (rogue fibrils) from various homozygous scrapie backgrounds. What they found happily was that quantitative in vitro conversion correlated quite well with incubation period for scrapie. Note also:
1. In Figure 3b, note AQ/AQ PrP Sc is actually better at hetero-conversion than at homo-conversion: more VQ prion than AQ prion in the tunicamycin D lanes [inhibits carobhydrate attachment]. Glycosylation is hard to interpret because who knows what it is being attached or what relation it has to what is normally attached, there being 400 variants in the one situation where anyone actually looked at the carbohydrate. Plus it is on the wrong side of the molecule and probably intensely hydrogen-bonded solvated off the protein surface with little influence (still, some) on protein conformation. I expect it to vary dramatically from one species to the next) and one brain cell type to the next, and one individual to the next (think of ABO blood groups, never mind who would want a blood transfusion from a sheep).
This is apparently the first instance of a negative species barrier, where transmission is actually worse cross-species than it is within-species. (Species of protein is meant here.) I predicted this some time ago. Alleles engineered for mild denaturation could do this much more dramatically [see below].
2. On the Prp Sc prepared from heterozygous AV/VQ sheep: based on CJD mixed amyloid, this probably would consist of a large number of molecular species of PrPSc seed fibers. I see possibilities for hetero-oligomers with a continuously variable composition parameter, like a mineral, in addition to pure fibers of both types. The hybrids have unpredictable, not necessarily intermediate properties, because they could have a cooperative conformational change making them into a slightly new strain type, enough for very different recruitment capabilities. I am looking through the transthyretin stuff to see if they have already documented this effect in their 50+ amyloid strain types . See review of the "other" 15 congophilic disorders.
What a mess this is at the level of pooled products from many animals such as sausage or hamburger -- there's no hope for an absolute species barrier with so many variations on the PrP Sc rogue seed fiber, just hope for slow net conversion relative to lifespan.
Here's a quick and sensitive assay for the infectious titre of various foodstuffs and biologics. It's as easy as 1-2-3:
1. Amplifcation: Just as PCR amplifies a very tiny amount of DNA to easily detectable levels, a small amount of Prp Sc can be amplified by flooding it with large amounts of normal prion under favorable conditions and measuring the final amount of protease resistant product, relative to control blanks, on gels. The product of course is not copies of the original Prp Sc but rather is comprised mainly of fibers of substrate prion chains. This turns the methods of the Bossers et al. paper on its head: determine whether Prp Sc was initially present at all and if so, how much.
2. Sensitivity: By saturation mutagenisis of prion genes on vectors, a prion variant can be sought that is extraordinaly sensitive to to the conversion process, shortening the time needed for incubation and lowering the threshhold on the level of initial PrpSc that can be detected. A somewhat contradictory property of this variant is its need to be stable under the conditions of the assay so that it doesn't form PrpSc on its own. In other words, the variant is a hair-trigger, fail-safe conformer. A cocktail of mixed variants might provide an all-in-one test of many source Prp Sc or a variant probe sensitized for whatever is suspected (ie, catches BSE but ignores scrapie) or only for what has human health implications (converting activity on human prions) could be used.
3. Identification/sourcing: Differant aliquots are probed by a large number of stock standard test sequences of normal prions and custom variants. The amounts and ratios of product provide a signature that allow the original rogue prion and its strain type to be identified or ruled out (provided signatures of many known Prp Sc sources have already been determined).
4. And of course there are excellent possibilities for rapid in vitro screening of therapeutic agents.
The above method won't help with diagnosis of incipient disease because a brain biopsy would be neeeded, though it could help determine incidence and describe degree of disease progression at autopsy more sensitively than microscopy or immuno-staining.
Nor does the method shed light on what level of positive titre would be a problem or how much cumulative positive titre would be safe to eat over a lifetime to still stop short of having symptoms. It just measures the positive titre, allows for this to be put on the food label, and lets people make informed choices. It also may allow direct testing of medicinals and biologics such a blood products, to whatever the threshold is for the mehtod.
J. Biol. Chem. 1997 June 13 272(24). 15227. Richard A. Bessen, Gregory J. Raymond, Byron CaugheyThe transmissible spongiform encephalopathies (TSEs) comprise a group of fatal neurodegenerative diseases that are characterized by the conversion of the normal host cellular prion protein (PrPC), to the abnormal protease-resistant prion protein isoform (PrP-res). It has been proposed, though not proven, that the infectious TSE agent consists solely of PrP-res and that PrP-res-induced conformational conversion of PrPC to additional PrP-res represents agent replication. In this study we demonstrate in situ conversion of protease-sensitive PrPC to PrP-res in TSE-infected brain slices. One step in this process is the binding of soluble PrPC to endogenous PrP-res deposits. The newly formed PrP-res associated with the slices in a pattern that correlated with the pre-existing brain distribution of PrP-res. Punctate in situ PrP conversion was observed in brain regions containing PrP-res amyloid plaques, and a more dispersed conversion product was detected in areas containing diffuse PrP-res deposits. These studies provide direct evidence that PrP-res formation involves the incorporation of soluble PrPC into both nonfibrillar and fibrillar PrP-res deposits in TSE-infected brain. Our findings suggest that the in situ PrP conversion reaction leads to additional polymerization of endogenous PrP-res aggregates and is analogous to the process of PrP-res fibril and subfibril growth in vivo.
Science 12 June 1997 Michael Babcock, ... Massimo Pandolfo, Jerry KaplanThe gene responsible for Friedreich's ataxia, a disease characterized by neurodegeneration and cardiomyopathy, has recently been cloned and its product designated frataxin. A gene in Saccharomyces cerevisiae was characterized whose predicted protein product has high sequence similarity to the human frataxin protein. The yeast gene (yeast frataxin homolog, YFH1) encodes a mitochondrial protein involved in iron homeostasis and respiratory function. Human frataxin also was shown to be a mitochondrial protein. Characterizing the mechanism by which YFH1 regulates iron homeostasis in yeast may help to define the pathologic process leading to cell damage in Friedreich's ataxia.
Nature 387, 717 721 (1997) R D Klein, D Sherman, W-H Ho, ... A RosenthalGlial-cell-line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two structurally related, potent survival factors for sympathetic, sensory and central nervous system neurons. GDNF mediates its actions through a multicomponent receptor system composed of a ligand- binding glycosyl-phosphatidylinositol (GPI)-linked protein (designated GDNFR-alpha) and the transmembrane protein tyrosine kinase Ret. In contrast, the mechanism by which the NTN signal is transmitted is not well understood. Here the authors describe the identification and tissue distribution of a GPI-linked protein (designated NTNR-alpha) that is structurally related to GDNFR-alpha. They further demonstrate that NTNR-alpha binds NTN (Kd~10pM) but not GDNF with high affinity; that GDNFR-alpha binds to GDNF but not NTN with high affinity; and that cellular responses to NTN require the presence of NTNR-alpha. Finally, they show that NTN, in the presence of NTNR-alpha, induces tyrosine-phosphorylation of Ret, and that NTN, NTNR-alpha and Ret form a physical complex on the cell surface. These findings identify Ret and NTNR-alpha as signalling and ligand-binding components, respectively, of a receptor for NTN and define a novel family of receptors for neurotrophic and differentiation factors composed of a shared transmembrane protein tyrosine kinase and a ligand-specific GPI-linked protein.
Nature 387, 569 (1997) K Simons & E IkonenA new aspect of cell membrane structure is presented, based on the dynamic clustering of sphingolipids and cholesterol to form rafts that move within the fluid bilayer. It is proposed that these rafts function as platforms for the attachment of proteins when membranes are moved around inside the cell and during signal transduction.
Nature 387,333 M. Kłng, B. Stadelmann, U. Brodbeck and P. Błtikofer
No To Shinkei 49 (5): 460-464 (May 1997) Kawauchi Y, Okada M, Kuroiwa Y, Ishihara O, Akai JWe report two brothers with familial Creutzfeldt Jakob disease (CJD) having a heterozygous point mutation at codon 200 of the prion protein gene (Glu-->Lys): CJD200. The brothers were born in Kitakoma-gun, Yamanashi Prefecture. Patient 1, a 62-year-old man, developed CJD in 1995 and died nine months later. Patient 2, his brother, developed CJD200 at the age of 58 in 1982 and died 13 months later. They both exhibited rapidly progressive dementia with myoclonus and periodic synchronous discharges on electroencephalograms and became bedridden with three or four months. DNA analysis of peripheral blood cells of patient I showed a point mutation in the prion protein gene at codon 200: GAG-->AAG (Glu-->Lys). Five families with CJD200, 11 patients, have been reported in Japan to date, and nine of the patients from four families were born in Yamanashi Prefecture and vicinity. Our patients were born in the same area.
The story below does not make a whole lot of sense -- why would a rancher want to help establish that mad cow disease was on his ranch or in the US? The idea would be if thousands of samples were sent in and they were all 14-3-3 negative, they could say it supported the concept of low levels of BSE in the US. But what if a fraction of a percent tested positive? The test itself has nothing to do with measuring infectivity titres per se but rather detects an unrelated protein that appears specifically in CSF after CNS neuronal damage in CJD.
The good points of the test are that it can be done on live animals and that it may pick up disease somewhat ahead of overt symptoms. The sensitivity will be poor compared to Bossers et al. direct measurement in vitro of rogue prion recruiting capability.
Thu, Jun 12, 1997 Business Wire Business & News Editors/Health & Science WritersPASADENA/DAVIS, Calif.-- Appeal to American beef growers made by scientists at California Institute of Technology and University of California, Davis:
Researchers who have developed a test for Mad Cow Disease are now working to refine that test for use in cattle as well as develop a test for the disease in humans. With accurate and conclusive diagnostic tests, veterinarians and physicians will be able to isolate and prevent the spread of these deadly diseases in animals and humans. Researchers are now making an urgent appeal to cattle ranchers for brain and spinal-tap samples.
``Today we are announcing an all-out effort to obtain brain and spinal-tap samples from cattle. We want veterinarians and cattle ranchers to work with us, using our protocol, to obtain tissue samples from cattle,'' said Michael Harrington, M.D., a neurologist at the California Institute of Technology in Pasadena.Harrington and three of his colleagues from the National Institutes of Health reported their results last September in the New England Journal of Medicine (Volume 335, pages 924-930, 1996). Harrington's lab recently published the first testing of U.K. cattle with this assay in the February issue of The Veterinary Record (Volume 140, pages 206-207, 1997).
``We are pleased to be joining forces to aid research into Mad Cow Disease. Working together, we think we can speed the research process and prevent the European experience from happening here in the United States,'' said Robert Higgins, D.V.M., Ph.D., a veterinary neuropathologist at the University of California, Davis, College of Veterinary Medicine.The protocol for obtaining tissue samples involves spinal-fluid collection from live animals, coupled with brain collection for neuropathology. Further details should be discussed with Harrington and Higgins.
Free information on Mad Cow Disease is available to veterinarians and cattle ranchers who call Dr. Lily Yang's office in Los Altos, Calif., at 415/917-0401; fax 415/917-1434; e-mail.
In England, more than 5 million cattle have been slaughtered at a cost of $700 million. Here in the United States, Neuromark Corp. of Los Altos is working to make the new test invented at Caltech (called 14-3-3) widely available to the beef-cattle industry and to physicians who wish to use it as a diagnostic tool.
There are more than 100 million beef cattle in the United States, with 26 million processed for beef a year, plus 30 million dairy cows. This is approximately 10 times more animals processed than in England.
An information hot line has been established (800/600-7111, ext. 234) for food processors, health-care providers and other professionals interested in the latest information on Mad Cow Disease and CJD. Callers will be added to an e-mail and mailing list and sent continuous updates as research progresses.
CONTACT: Halsted Communications, Los Angeles John Lockhart, 800/600-7111, ext. 224 213/957-3111, ext. 224
They identified nineteen cases of spongiform encephalopathy (characteristic CJD) of which only eleven were clinically diagnosed before death. As the authors point out, these results have to be interpreted with caution because they are not representative of the population, but it does indicate that, in SE England in that period, even among people exhibiting some form of dementia, of the order of more than half were not diagnosed in life as CJD.
It is of course true that since the formation of the CJDSU in 1990, and more especially since Robert Will's widely circulated letter in March 1996, far more cases than previously, of possible CJD are clinically spotted in life and referred to CJDSU.
Heynkes wrote on 6 June 1997
Only a very small portion of TSE research has been published in the Veterinary Record [Journal of the British Veterinary Association]. Among my 4687 database records only 216 are from this journal.
9 Jun 1997 commentary by WebmasterThe genotype of Jakob's original patient: This would seem to be the Backer family. They were looked at again in 1950 by Jakob and later by other researchers [refs below]. At OMIM, a huge and well-edited compilation of all human genetic disorders, they are carrying the genotype of later descendants as D178N val/val. There is a slight amount of ambiguity about the exact haplotypes. That is, there are 10 very distinct genotypes here, depending on how the codon changes are paired over the diploid genome:
met-asp; met-asp "wild type" (based on other primates) met-asp; met-asn FFI met-asn; met-asn not seen, homozygous FFI met-asp; val-asp "wild type" with a neutral heterozygous polymorphism met-asp; val-asn Jakob CJD with a wild type heterozygous polymorphism met-asn; val-asp FFI with a neutral heterozygous polymorphism met-asn; val-asn simultaneous FFI + Jakob CJD val-asp; val-asp "wild type with a neutral homozygous polymorphism" val-asp; val-asn Jakob CJD with a neutral homozygous polymorphism (Backer family?) val-asn; val-asn not seen, homozygous Jakob CJDSince there are many other mutations besides 178 asn and many other polymorphisms besides 129 met/val, the number of underlying genotypes is astronomical. In fact, we may have enough so that everyone on the planet can be famous for 15 minutes by having a potentialy occuring variant named after themselves.
I don't see any movement in the biomedical literature towards JCD or JD. GSS and FFI are fairly specific while CJD is a large bucket that gets all the slop, phenotypic and genotypic.
I propose to move over to "prionopathy" with a specified genotype, that is, "prionopathy M129M D178N" for FFI and so on for a uniform nomenclature. If we specify enough of the genotype, the phenotype will follow.
Prionopathies are unusual, but hardly unprecedented, in that the disease state arises from oligomeric recruitment. So the primary, secondary, and tertiary structures, as well as any and all post-translational modifications, of all relevent prion structures on the scene over time, do matter.
We may need further nomenclature to describe the initial recruiting rogue prion, which might be from another vertebrate, to handle strain types, which seem to be variants in quaternary amyloid. Again, there are 16 unrelated human amyloid disorders and strain types are also found in these [transthyretin etc.].
Ideally, nomenclature would be uniform across all 16 congophilic disorders.
Note the prion protein, unlike the others, finds itself on the outside cell surface, and so is exposed to exogenous prions that might migrate up lipid bilayer of PNS as well as to 109-125 recruiting fragments. A cytoplasmic congophile is exposed only to endogenously generated conformers, regardless of what is in the diet. In other words, "infectivity' may follow from the happenstance of cellular distribution and a chameleon helix or two.
So an (extreme and hypothetical) example of my final proposal is "human prionopathy M129M D178N [bovine R5 [ovine Q171R]] " for a case of nvCJD in a person already predisposed to FFI triggered by a rogue bovine prion from an extra octapeptide repeat cow, which had acquired BSE from a sheep with a predisposition to scrapie.becasue of an arginine at sheep codon 171.
This isn't just overly pedantic bookkeeping because we may need eventually to tailor the therapeutic agent to the needs of the individual patient, if the goal is capping off or dissolving rogue seed fibers.
Finally, we need to drive a wooden stake through the heart of the prion seed "crystal" before this gets any further entrenched. Amyloid fibers, oligomers, and aggregates are not, repreat not, crystals in the century-old sense of having a space group. Sure, prion fibers have periodicity over the dimer and so a one dimensional translation-with-a-twist symmetry, but we already have a perfectly good word for this: helix. If multiple fibers specifically associate, we have fiber or helix bundle; if it's not so specific, there's always amyloid.Old nomenclatures, like old prions, are hard to inactivate, so I don't expect this proposal to go anywhere, whatever the merits and refinements!
Jakob, H.; Pyrkosch, W.; Strube, H. : Hereditary form of Creutzfeldt-Jakob disease (Backer family). Arch. Psychiat. 184: 653-674, 1950.