Viruses. 2022 Feb; 14(2): 367.
Published online 2022 Feb 10. doi: 10.3390/v14020367
PMCID: PMC8879235
PMID: 35215959
Phenotypic Heterogeneity of Variably Protease-Sensitive Prionopathy: A Report of Three Cases Carrying Different Genotypes at PRNP Codon 129
Simone Baiardi,1,2 Angela Mammana,1,2 Marcello Rossi,1 Anna Ladogana,3 Benedetta Carlà,1 Pierluigi Gambetti,4 Sabina Capellari,1,5 and Piero Parchi1,2,*
Christina Sigurdson, Academic Editor
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Abstract
Variably protease-sensitive prionopathy is an exceedingly rare, likely underestimated, sporadic prion disease that is characterized by heterogeneous and often non-specific clinical and pathological features posing diagnostic challenges. We report the results of a comprehensive analysis of three emblematic cases carrying different genotypes at the methionine (M)/valine (V) polymorphic codon 129 in the prion protein gene (PRNP). Clinical, biochemical, and neuropathological findings highlighted the prominent role of the host genetic background as a phenotypic modulator. In particular, the PRNP codon 129 showed a remarkable influence on the physicochemical properties of the pathological prion protein (PrPSc), especially on the sensitivity to proteinase K (PK) digestion (VV > MV > MM), which variably affected the three main fragments (i.e., of 19, 17, and 7 kDa, respectively) comprising the PrPSc profile after PK digestion and immunoblotting. This, in turn, correlated with significant differences in the ratio between the 19 kDa and the 7 kDa fragments which was highest in the MM case and lowest in the VV one. The relative amount of cerebral and cerebellar PrP mini-plaques immunohistochemistry showed a similar association with the codon 129 genotype (i.e., VV > MV > MM). Clinical manifestations and results of diagnostic investigations were non-specific, except for the detection of prion seeding activity by the real-time quaking-induced conversion assay in the only cerebrospinal fluid sample that we tested (from patient 129VV).
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4. Discussion
VPSPr, the last identified human prion disease, still represents a puzzling entity because of its rarity and the significant heterogeneity of its clinical and histo-molecular features. The present work supports the current view that the genotype at codon 129 plays an essential role in determining the phenotypic diversity in VPSPr.
In line with previous studies [11,30], we found that VPSPr PrPSc shows the highest sensitivity to PK digestion in individuals 129VV, the lowest in those carrying 129MM, and intermediate values in those with 129MV. We also confirmed that VPSPr PrPSc shows an overall distinctive immunoblot profile, but with an additional significant heterogeneity among cases depending on the PK activity and the codon 129 genotype [31]. Overall, both 3F4 and T2 antibodies detect five PrPSc fragments independent from the codon 129 genotype, including mono- and un-glycosylated forms of a 19 kDa fragment corresponding to CJD PrPSc type 2, monoglycosylated and unglycosylated forms of a 17 kDa fragment lacking the GPI anchor and a 7 kDa fragment ragged at both N- and C-termini.
Our comparison of the PrP immunoblot profile between the TH and a P3 fraction of sarkosyl-insoluble full-length PrPSc demonstrated that all three PrPC glycoforms are normally expressed in VPSPr brains and that the lack of the diglycosylated isoform is a specific feature of VPSPr PrPSc related to the lack of conversion of diglycosylated PrPC into PrPSc. The finding further supports the current view that strain-specific PrPSc structural constraints may determine the selective recruitment of PrPSc glycoform favoring those with reduced or no glycan chains, shifting the ratios of glycoforms within PrPSc toward mono- and un-glycosylated glycoforms [32].
Of note, we found that the relative proportion of the three unglycosylated PrPSc fragments is significantly associated with the codon 129 genotype. The relatively high representation and high PK resistance of the 19 kDa band in the 129MM brain make this case the most “CJD-like” among the three. On the opposite side, the PrPSc that is associated with 129VV showed the most atypical profile, characterized by the rapid disappearance of PrPSc type 2 due to its high PK sensitivity, a slightly faster migration of the 17 kDa fragment, and the highest intensity of the 7 kDa band. It is well established that similar PrPSc fragments also characterize the so-called inherited prion protein amyloidoses, including Gerstmann-Sträussler-Scheinker disease (GSS), and the cerebral and systemic amyloidosis that are linked to stop-codon truncating PRNP mutations [33]. Although PrPSc does not accumulate as amyloid in VPSPr, it is noteworthy that the amount of PrP mini-plaques that were seen at immunochemistry has been linked to the relative amount of the 7 kDa fragment (VV > MV > MM) [11] [present work]. Further similarities between GSS and VPSPr are the relatively long disease duration and the lack of efficient transmission to transgenic mice expressing human PrP [34,35].
In VPSPr, the different PrPSc biochemical properties influence the clinicopathological features, including the disease duration, spongiform change severity, and PrP deposition pattern at immunohistochemistry. Conversely, the type of spongiform change, characterized by small and intermediate vacuoles and the lesion distribution profile, appear consistent across codon 129 genotypes. The short duration that is associated with very mild spongiform change and the sparing of the cerebellum in our 129MV case are unlikely related to the natural history of the disease, but rather depend on the early occurrence of medical complications, such as fever and hypertensive crisis, that lead to the early death of the patient.
In our case series, the clinical presentations were heterogeneous, largely non-specific, and included a variable combination of cognitive, psychiatric, and cerebellar signs. Prion disease (i.e., CJD) was only suspected in the 129VV case, whereas other alternative diagnoses were AD in the 129MV case and atypical multiple system atrophy in the patient carrying 129MM. Both the EEG and brain MRI disclosed non-specific and inconclusive findings. CSF analyses were performed only in the 129VV case: the positivity of 14-3-3 protein raised the suspicion of CJD, but the concurrently increased levels of p-tau and decreased Aβ ratio prompted the diagnosis of AD. In this context, the detection of prion seeding activity by CSF RT-QuIC steered the diagnosis in the direction of prion disorder. Despite the limited number of cases that were analyzed, CSF RT-QuIC seems to have a good performance in VPSPr, being positive in five out of six patients (83.3%) that were tested using the truncated rPrP [19,36]. Future studies should confirm this initial evidence in larger cohorts, since the specificity of prion RT-QuIC makes the assay a suitable diagnostic tool to identify novel VPSPr cases clinically.
We also investigated VPSPr brains for neurodegenerative co-pathologies. We detected CAA and a low burden of AD neuropathologic change [37] in the older patients (129MV and VV). Various degrees of Aβ-immunoreactivity have been previously reported in VPSPr and attributed to aging [9,11]. Co-existence of widespread neocortical Lewy bodies, mild AD neuropathologic change, and CAA have previously been reported in a single VPSPr-129MV patient [38]. Besides tau neurofibrillary pathology, we detected ARTAG pathology in the 129VV case. Prominent gray matter ARTAG was previously reported in sporadic and genetic CJD [39], but not in VPSPr. Further studies are needed to confirm the consistency of this association.
Finally, Case#1 of our series deserves a particular comment being the first case of the disease that was later identified and named VPSPr, which was recognized as an atypical novel human prion disease phenotype that was not classifiable within the sCJD spectrum [40].
Go to: 5. Conclusions The present study strengthens previously published evidence that, in VPSPr, the PRNP codon 129 has a remarkable influence on pathologic and biochemical features, and, to a lesser extent, on clinical presentation. This variability makes both clinical and neuropathologic diagnosis challenging. On the one hand, neuropathologists should raise the suspicion of VPSPr when intermediate sized vacuoles and PrP mini-plaques or small plaque-like deposits are identified, even in front of an apparently “negative” result of PrPSc typing by Western blot. On the other hand, neurologists should consider VPSPr in the differential diagnosis with other forms of dementia that are associated with motor/behavioral symptoms, in particular frontotemporal dementia, and atypical forms of AD. The detection of CSF prion seeding activity by RT-QuIC in the single VPSPr patient that we tested (129VV) is consistent with the few other reports that are available in the literature, suggesting that RT-QuIC might be a useful tool for the identification of this rare and puzzling disease in vivo.
Go to: Acknowledgments We wish to thank Barbara Polischi for the valuable technical assistance. We are also grateful to Tetsuyuki Kitamoto (Tohoku University, Sendai, Japan) and Bernardino Ghetti (Indiana University, Indianapolis, IN USA) for providing the T2 and the anti-PrP 23–40 antibodies, respectively.
Go to: Supplementary Materials The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/v14020367/s1, Figure S1: Analysis of protease resistance of PrPSc by PK titration assay in a sCJD VV2 brain.
Click here for additional data file.(333K, zip) Go to: Author Contributions Conceptualization, P.P.; methodology, P.P.; formal analysis and investigation, S.B., A.M., M.R., A.L., B.C., P.G., S.C. and P.P.; writing—original draft preparation, S.B. and P.P.; writing—review and editing, all authors; supervision, P.P.; project administration, P.P.; funding acquisition, P.P. All authors have read and agreed to the published version of the manuscript.
Go to: Funding This work was financially supported by the Italian Ministry of Health grant “Ricerca Corrente” and the University of Bologna grants “Ricerca Fondamentale Orientata (RFO)” to P.P.
Go to: Institutional Review Board Statement The study was conducted according to the guidelines of the Declaration of Helsinki; all medical information was collected as part of national surveillance programs for prion diseases and approved by the Institutional Review Board at Istituto Superiore di Sanità (CE-ISS 09/266, May 2009).
Go to: Informed Consent Statement
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WHY do some countries count vpspr as sporadic cjd tse prion, and some countries don't?
THIS problem must be addressed immediately imo.
WE have the USA classifying Variably protease-sensitive prionopathy (VPSPr) (formerly known as Protease Sensitive Prionopathy) as sporadic Creutzfeldt Jakob Disease sCJD, and we have Canada not even mentioning in on there statistics links, like vpspr does not even exist, so this is a problem for any valid surveillance imo. IN fact, personal communication from Canada Surveillance et al;
QUOTE;
''Well Terry, we have the data. We simply do not report it separately because we do not believe it has any specific epidemiologic significance, including zoonotic transmission (this opinion is shared unanimously by the international CJD surveillance community, and was established very quickly after the discovery of VPSPr). The key reason in my mind why the US system reports it – in a footnote to their sporadic CJD data – is that they discovered it, and want to follow up on it publicly to validate the reality of their finding scientifically (which is distinct from its significance).''
''The simple answer to your question is that we do not track VPSPr separately, as we view is as a form of sporadic CJD with an unusual phenotype but no specific epidemiological significance. Even the USA surveillance figures do not report it separately.''
end
Hell of a way for a surveillance system for any country to look for any suspect unusual zoonosis zoonotic disease from any mutated TSE Prion strain from any species.
OH, that's right, Canada is already investigating a mystery cjd (like) brain disease, that mimics CJD, from what the papers media are saying, but doctors are saying it's not CJD. MY POINT is, VPSPR, and how Canada is treating that vs USA. just smells fishy to me, what if vpspr was some how related to CWD TSE Prion, or an iatrogenic event there from? do we know with certainty that vpspr tse prion is not a zoonosis disease?
especially considering, with the diagnostic criteria still set up for the UKBSEnvCJD only theory, and all other human tse prion disease a sporadic spontaneous event, just appears to me that no one wants to find another zoonotic TSE Prion disease, even though the science is staring them in the face stating otherwise, with Chronic Wasting Disease CWD TSE PrP of Cervid being a highly likely source of some cases of the sporadic cjd's.
Having better diagnostic tools to diagnose human TSE Prion disease is a great thing, we must use them, but continuing to use the old UKBSEnvCJD only diagnostic criteria to differentiate between everything other than typical c-type BSE and nvCJD, when there is a world of science saying otherwise, will only continue to spread the TSE Prion agent, imo...terry
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.
Terry S. Singeltary, Sr Bacliff, Tex
1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323.
Creutzfeldt Jakob Disease CJD TSE Prion Update December 25, 2021
Tables of Cases Examined National Prion Disease Pathology Surveillance Center Cases Examined¹
Updated quarterly.
Last updated on: December 10th, 2021
Year Total Referrals² Prion Disease Sporadic Familial Iatrogenic vCJD
1999 & earlier 383 231 201 27 3 0
2000 145 102 90 12 0 0
2001 209 118 110 8 0 0
2002 241 144 124 18 2 0
2003 259 160 137 21 2 0
2004 315 180 163 16 0 1³
2005 328 179 157 21 1 0
2006 365 179 159 17 1 2⁴
2007 374 210 191 19 0 0
2008 384 221 205 16 0 0
2009 397 231 210 20 1 0
2010 401 246 218 28 0 0
2011 392 238 214 24 0 0
2012 413 244 221 23 0 0
2013 416 258 223 34 1 0
2014 355 208 185 21 1 1⁵
2015 401 263 243 20 0 0
2016 395 277 248 29 0 0
2017 375 266 247 19 0 0
2018 308 221 202 18 1 0
2019 432 280 259 21 0 0
2020 362 250 225 24 1 0
2021 282 183 157 15 0 0
TOTAL 79326 48897 43898 4609 14 4
1Listed based on the year of death or, if not available, on the year of referral;
2Cases with suspected prion disease for which brain tissue was submitted;
3Disease acquired in the United Kingdom;
4Disease acquired in the United Kingdom in one case and in Saudi Arabia in the other;
5Disease possibly acquired in a Middle Eastern or Eastern European country;
6Includes 35 cases in which the diagnosis is pending (1 from 1999, 2 from 2020 and 32 from 2021), and 19 inconclusive cases;
7Includes 11 (11 from 2021) cases with type determination pending in which the diagnosis of vCJD has been excluded.
8The sporadic cases include 4276 cases of sporadic Creutzfeldt-Jakob disease (sCJD), 76 cases of Variably Protease-Sensitive Prionopathy (VPSPr) and 37 cases of sporadic Fatal Insomnia (sFI).
9Total does not include 291 Familial cases diagnosed by blood test only.
***> 6Includes 35 cases in which the diagnosis is pending (1 from 1999, 2 from 2020 and 32 from 2021), and 19 inconclusive cases;
***> 7Includes 11 (11 from 2021) cases with type determination pending in which the diagnosis of vCJD has been excluded.
***> 8The sporadic cases include 4276 cases of sporadic Creutzfeldt-Jakob disease (sCJD),
***> 76 cases of Variably Protease-Sensitive Prionopathy (VPSPr) and 37 cases of sporadic Fatal Insomnia (sFI).
***> CANADA NO VPSPR ???
CANADA CJD TSE PRION
Referrals of suspected CJD reported by CJDSS, 1998-2021 As of November 30, 2021
Year of reporting Number of referrals
1998 43
1999 63
2000 82
2001 101
2002 103
2003 75
2004 90
2005 97
2006 80
2007 101
2008 100
2009 104
2010 76
2011 102
2012 103
2013 99
2014 99
2015 98
2016 117
2017 116
2018 125
2019 142
2020 123
2021 119
Total 2358
Definite and probable CJD, 1998-2021 As of November 30, 2021
Year Sporadic Iatrogenic CJD Genetic vCJD Total
1998 22 1 1 0 24
1999 27 2 3 0 32
2000 32 0 3 0 35
2001 27 0 3 0 30
2002 31 0 2 1 36
2003 27 1 1 0 29
2004 42 0 4 0 44
2005 42 0 2 0 44
2006 39 0 5 0 44
2007 35 0 4 0 39
2008 48 0 1 0 49
2009 48 0 5 0 53
2010 35 0 3 0 38
2011 46 0 4 1 51
2012 62 0 1 0 63
2013 50 0 1 0 51
2014 51 0 5 0 56
2015 44 0 8 0 52
2016 57 1 6 0 64
2017 82 0 5 0 87
2018 75 1 5 0 81
2019 76 0 2 0 78
2020 61 0 4 0 65
2021 21 0 1 0 23
Total 1080 6 80 2 1168
CJD deaths in Canada
Year of death Total CJD cases Population of Canada Crude mortality rate
1998 24 30,244,982 0.79
1999 32 30,492,106 1.05
2000 35 30,783,969 1.14
2001 30 31,130,030 0.96
2002 36 31,450,443 1.14
2003 29 31,734,851 0.91
2004 44 32,037,434 1.37
2005 44 32,352,233 1.36
2006 44 32,678,986 1.35
2007 39 33,001,076 1.18
2008 49 33,371,810 1.47
2009 53 33,756,714 1.57
2010 38 34,131,451 1.11
2011 51 34,472,304 1.48
2012 63 34,880,248 1.81
2013 51 35,289,003 1.45
2014 56 35,675,834 1.57
2015 52 35,702,707 1.46
2016 64 36,286,400 1.76
2017 86 36,712,658 2.37
2018 80 37,589,262 2.15
2019 78 37,802,043 2.06
Cases with definite and probable diagnosis to date
Population estimates as of July each year (Statistics Canada population estimates, quarterly)
why has Canada not detected not one case of VPSPR TSE PRION ???
FRIDAY, DECEMBER 24, 2021
Creutzfeldt Jakob Disease CJD TSE Prion Update December 25, 2021
97. In vitro seeding activity of glycoform-deficient prions from variably protease-sensitive prionopathy and familial CJD associated with PrPV180I mutation
Zerui Wanga,b, Jue Yuana, Pingping Shena,b, Romany Abskharonc, Yue Langa,b, Johnny Danga, Alise Adornatoa, Ling Xua, Jiafeng Chenb, Jiachun Fengb, Mohammed Moudjoud, Tetsuyuki Kitamotoe, Jan Langeveldf, Brian Applebya,g,h, Jiyan Mac, Qingzhong Konga,g,h, Robert B. Petersena,i, Li Cuib and Wen-Quan Zoua,b,g,h
aDepartment of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; bDepartment of Neurology, The First Hospital of Jilin University, Changchun, Jilin Province, the People’s Republic of China; cCenter for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA; dNRA, Université Paris-Saclay, UR892, Virologie Immunologie Moléculaires, Jouy-en-Josas, France; eCenter for Prion Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan; fWageningen BioVeterinary Research, Lelystad, the Netherlands; gNational Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA; 8Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH, USA; iFoundation Sciences, Central Michigan University College of Medicine, Mount Pleasant, MI, USA
ABSTRACT
Both sporadic variably protease-sensitive prionopathy (VPSPr) and familial Creutzfeldt-Jakob disease linked to the prion protein (PrP) V180I mutation (fCJDV180I) have been found to share a unique pathological prion protein (PrPSc) pattern that lacks the protease-resistant PrPSc glycosylated at residue 181, apparently because two of four cellular PrP (PrPC) glycoforms are not converted into PrPSc. To investigate the seeding activity of these unique PrPSc molecules, we conducted in vitro prion conversion experiments using serial protein misfolding cyclic amplification (sPMCA) and real-time quaking-induced conversion (RT-QuIC) assays with different PrPC substrates. Unexpectedly, we observed that the seeding of PrPSc from VPSPr or fCJDV180I in the sPMCA reaction with brain homogenates from normal human or humanized transgenic (Tg) mice generated PrPSc molecules that are dominated by the diglycosylated isoform, along with PrPSc monoglycosylated at residue 181. The efficiency of PrPSc amplification was significantly higher in MM than in VV human brain homogenate, whereas it was higher in TgVV than in TgMM mouse brain homogenate. PrPC from the brain homogenate mixture of TgMM and Tg mice expressing PrPV180I mutation (Tg180), but not that from TgV180I alone, was converted into PrPSc by seeding with the VPSPr or fCJDV180I. The RT-QuIC seeding activity of PrPSc from VPSPr and fCJDV180I was significantly lower than that of sCJD. Our results suggest that the formation of glycoform-selective prions may be associated with an unidentified factor in the affected brain and the glycoform-deficiency of PrPSc does not affect the glycoforms of in vitro newly-amplified PrPSc
Funding
Supported in part by the CJD Foundation and the National Institutes of Health (NIH) NS062787 and NS087588 to W.Q.Z., NS062787 and NS109532 to W.Q.Z., and Q.K., NS088604 to Q.K., the Centers for Disease Control and Prevention Contract UR8/CCU515004 to B.S.A., the National Natural Science Foundation of China (NNSFC) [No. 81,801,207] to PS, as well as NNSFC [No. 81,671,186] to LC.
Volume 25, Number 1—January 2019
Research
Variable Protease-Sensitive Prionopathy Transmission to Bank Voles
Romolo Nonno1, Silvio Notari1, Michele Angelo Di Bari, Ignazio Cali, Laura Pirisinu, Claudia d’Agostino, Laura Cracco, Diane Kofskey, Ilaria Vanni, Jody Lavrich, Piero Parchi, Umberto Agrimi, and Pierluigi GambettiComments to Author
Author affiliations: Istituto Superiore di Sanità, Rome, Italy (R. Nonno, M.A. Di Bari, L. Pirisinu, C. d’Agostino, I. Vanni, U. Agrimi); Case Western Reserve University, Cleveland, Ohio, USA (S. Notari, I. Cali, L. Cracco, D. Kofskey, J. Lavrich, P. Gambetti); University of Bologna, Bologna, Italy (P. Parchi); Istituto delle Scienze Neurologiche di Bologna, Bologna (P. Parchi)
Abstract
Variably protease-sensitive prionopathy (VPSPr), a recently described human sporadic prion disease, features a protease-resistant, disease-related prion protein (resPrPD) displaying 5 fragments reminiscent of Gerstmann-Sträussler-Scheinker disease. Experimental VPSPr transmission to human PrP–expressing transgenic mice, although replication of the VPSPr resPrPD profile succeeded, has been incomplete because of second passage failure. We bioassayed VPSPr in bank voles, which are susceptible to human prion strains. Transmission was complete; first-passage attack rates were 5%–35%, and second-passage rates reached 100% and survival times were 50% shorter. We observed 3 distinct phenotypes and resPrPD profiles; 2 imitated sporadic Creutzfeldt-Jakob disease resPrPD, and 1 resembled Gerstmann-Sträussler-Scheinker disease resPrPD. The first 2 phenotypes may be related to the presence of minor PrPD components in VPSPr. Full VPSPr transmission confirms permissiveness of bank voles to human prions and suggests that bank vole PrP may efficiently reveal an underrepresented native strain but does not replicate the complex VPSPr PrPD profile.
Chapter 10 - Variably protease-sensitive prionopathy
Author links open overlay panel Silvio Notari1 Brian S.Appleby1234 Pierluigi Gambetti1
1 Department of Pathology, Case Western Reserve University, Cleveland, OH, United States
2 National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH, United States
3 Department of Neurology, Case Western Reserve University, Cleveland, OH, United States
4 Department of Psychiatry, Case Western Reserve University, Cleveland, OH, United States
Available online 7 June 2018.
Abstract
Variably protease-sensitive prionopathy (VPSPr), originally identified in 2008, was further characterized and renamed in 2010. Thirty-seven cases of VPSPr have been reported to date, consistent with estimated prevalence of 0.7–1.7% of all sporadic prion diseases. The lack of gene mutations establishes VPSPr as a sporadic form of human prion diseases, along with sporadic Creutzfeldt–Jakob disease (sCJD) and sporadic fatal insomnia. Like sCJD, VPSPr affects patients harboring any of the three genotypes, MM, MV, and VV at the prion protein (PrP) gene polymorphic codon 129, with VPSPr VV accounting for 65% of all VPSPr cases. Distinguishing clinical features include a median 2-year duration and presentation with psychiatric signs, speech/language impairment, or cognitive decline. Neuropathology comprises moderate spongiform degeneration, PrP amyloid miniplaques, and a target-like or plaque-like PrP deposition. The abnormal PrP associated with VPSPr typically forms an electrophoretic profile of five to seven bands (according to the antibody) presenting variable protease resistance depending on the 129 genotype. The familial prion disease associated with the V180I PrP gene mutation which harbors an abnormal PrP with similar electrophoretic profile might serve as a model for VPSPr. Transmission to animals has definitively established VPSPr as a prion disease. Because of its recent identification, rarity, and the elusiveness of its abnormal PrP, VPSPr remains largely understudied.
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Keywords
sensitive transmissible sporadic anchorless internal fragment psychiatric abnormalities speech impairment cognitive declinenormal-pressure hydrocephalus atypical dementia
*** Conclusions. Preliminary results from transmission studies in bank voles strongly support the notion that VPSPr is a transmissible prion disease. Interestingly, VPSPr undergoes divergent evolution in the two genetic lines of voles, with sCJD-like features in BvM109 and GSS-like properties in BvI109. The discovery of previously unrecognized prion diseases in both humans and animals (i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases might be wider than expected and raises crucial questions about the epidemiology and strain properties of these new forms. We are investigating this latter issue by molecular and biological comparison of VPSPr, GSS and Nor98.
OR-10: Variably protease-sensitive prionopathy is transmissible in bank voles
Romolo Nonno,1 Michele Di Bari,1 Laura Pirisinu,1 Claudia D’Agostino,1 Stefano Marcon,1 Geraldina Riccardi,1 Gabriele Vaccari,1 Piero Parchi,2 Wenquan Zou,3 Pierluigi Gambetti,3 Umberto Agrimi1 1 Istituto Superiore di Sanità; Rome, Italy; 2 Dipartimento di Scienze Neurologiche, Università di Bologna; Bologna, Italy; 3 Case Western Reserve University; Cleveland, OH USA
Background. Variably protease-sensitive prionopathy (VPSPr) is a recently described “sporadic”neurodegenerative disease involving prion protein aggregation, which has clinical similarities with non-Alzheimer dementias, such as fronto-temporal dementia. Currently, 30 cases of VPSPr have been reported in Europe and USA, of which 19 cases were homozygous for valine at codon 129 of the prion protein (VV), 8 were MV and 3 were MM. A distinctive feature of VPSPr is the electrophoretic pattern of PrPSc after digestion with proteinase K (PK). After PK-treatment, PrP from VPSPr forms a ladder-like electrophoretic pattern similar to that described in GSS cases. The clinical and pathological features of VPSPr raised the question of the correct classification of VPSPr among prion diseases or other forms of neurodegenerative disorders. Here we report preliminary data on the transmissibility and pathological features of VPSPr cases in bank voles.
Materials and Methods. Seven VPSPr cases were inoculated in two genetic lines of bank voles, carrying either methionine or isoleucine at codon 109 of the prion protein (named BvM109 and BvI109, respectively). Among the VPSPr cases selected, 2 were VV at PrP codon 129, 3 were MV and 2 were MM. Clinical diagnosis in voles was confirmed by brain pathological assessment and western blot for PK-resistant PrPSc (PrPres) with mAbs SAF32, SAF84, 12B2 and 9A2.
Results. To date, 2 VPSPr cases (1 MV and 1 MM) gave positive transmission in BvM109. Overall, 3 voles were positive with survival time between 290 and 588 d post inoculation (d.p.i.). All positive voles accumulated PrPres in the form of the typical PrP27–30, which was indistinguishable to that previously observed in BvM109 inoculated with sCJDMM1 cases. In BvI109, 3 VPSPr cases (2 VV and 1 MM) showed positive transmission until now. Overall, 5 voles were positive with survival time between 281 and 596 d.p.i.. In contrast to what observed in BvM109, all BvI109 showed a GSS-like PrPSc electrophoretic pattern, characterized by low molecular weight PrPres. These PrPres fragments were positive with mAb 9A2 and 12B2, while being negative with SAF32 and SAF84, suggesting that they are cleaved at both the C-terminus and the N-terminus. Second passages are in progress from these first successful transmissions.
Conclusions. Preliminary results from transmission studies in bank voles strongly support the notion that VPSPr is a transmissible prion disease. Interestingly, VPSPr undergoes divergent evolution in the two genetic lines of voles, with sCJD-like features in BvM109 and GSS-like properties in BvI109. The discovery of previously unrecognized prion diseases in both humans and animals (i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases might be wider than expected and raises crucial questions about the epidemiology and strain properties of these new forms. We are investigating this latter issue by molecular and biological comparison of VPSPr, GSS and Nor98.
8. Even though human TSE‐exposure risk through consumption of game from European cervids can be assumed to be minor, if at all existing, no final conclusion can be drawn due to the overall lack of scientific data. In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids. It might be prudent considering appropriate measures to reduce such a risk, e.g. excluding tissues such as CNS and lymphoid tissues from the human food chain, which would greatly reduce any potential risk for consumers. However, it is stressed that currently, no data regarding a risk of TSE infections from cervid products are available.
Subject: CWD GSS TSE PRION SPINAL CORD, Confucius Ponders, What if?
Saturday, February 2, 2019
CWD GSS TSE PRION SPINAL CORD, Confucius Ponders, What if?
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***> In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II) <***
REVIEW
***> In conclusion, sensory symptoms and loss of reflexes in Gerstmann-Sträussler-Scheinker syndrome can be explained by neuropathological changes in the spinal cord. We conclude that the sensory symptoms and loss of lower limb reflexes in Gerstmann-Sträussler-Scheinker syndrome is due to pathology in the caudal spinal cord. <***
***> The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology.<***
***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD. <***
***> All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals.<***
***> In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II) <***
Thursday, March 8, 2018
Familial human prion diseases associated with prion protein mutations Y226X and G131V are transmissible to transgenic mice expressing human prion protein
Saturday, February 2, 2019
CWD GSS TSE PRION SPINAL CORD, Confucius Ponders, What if?
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what if ???
Greetings Friends, Neighbors, and Colleagues,
FRIDAY, JANUARY 10, 2014
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???
Greetings Friends, Neighbors, and Colleagues,
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???
Confucius is confused again.
I was just sitting and thinking about why there is no genetic link to some of these TSE prion sGSS, sFFi, and it’s really been working on my brain, and then it hit me today.
what if, vpspr, sgss, sffi, TSE prion disease, was a by-product from iatrogenic gss, ffi, familial type prion disease ???
it could explain the cases of no genetic link to the gss, ffi, familial type prion disease, to the family.
sporadic and familial is a red herring, in my opinion, and underestimation is spot on, due to the crude prehistoric diagnostic procedures and criteria and definition of a prion disease.
I say again, what if, iatrogenic, what if, with all these neurological disorders, with a common denominator that is increasingly showing up in the picture, called the prion.
I urge all scientist to come together here, with this as the utmost of importance about all these neurological disease that are increasingly showing up as a prion mechanism, to put on the front burners, the IATROGENIC aspect and the potential of transmission there from, with diseases/disease???
in question, by definition, could they be a Transmissible Spongiform Encephalopathy TSE prion type disease, and if so, what are the iatrogenic chances of transmission?
this is very important, and should be at the forefront of research, and if proven, could be a monumental breakthrough in science and battle against the spreading of these disease/diseases.
again, sporadic and familial is a red herring, in my opinion.
also, in my opinion, when you start have disease such as sporadic Fatal Familial Insomnia, (and or sporadic GSS, or the VPSPr type prion disease), and there is NO familial genetic linkage to the family of the diseased, I have serious questions there as to a familial type disease, and thus, being defined as such.
*UPDATE* NOVEMBER 16, 2014 vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what if ???
Friday, January 10, 2014
Monday, August 9, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein or just more Prionbaloney ?
Wednesday, March 28, 2012
VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS TRANSMISSIBLE ...price of prion poker goes up again $
OR-10 15:25 - 15:40 VARIABLY PROTEASE-SENSITIVE PRIONOPATHY IS TRANSMISSIBLE IN BANK VOLES Nonno
O.10.5
A novel human prion disease affecting subjects with the three prion protein codon 129 genotypes: could it be the sporadic form of Gerstmann-Straussler?
Pierluigi Gambetti Case Western Reserve University, USA
Background: We recently described a novel prion disease, named protease-sensitive prionopathy or PSPr, characterized by the presence of an abnormal prion protein (PrP) that was 60 fold less protease resistant than that of sporadic Creutzfeldt-Jakob disease (sCJD) and on immunoblot generated a distinct ladder-like profile. All affected subjects where homozygous for valine at codon 129 (VV) and had no mutation in the PrP gene.
Methods: We have characterized several new cases in our surveillance and received from Europe.
Results: 1) A disease overall similar to that reported in the 129VV subjects also affects subjects that are methionine/valine heterozygous (MV) and methionine homozygous (MM) at codon 129 and have no PrP gene mutation; 2) The clinical and histopathological features of the new MV and MM PSPr cases are similar but distinguishable from those of the original VV cases; 3) The electrophoretic profiles generated by the abnormal PrP isoforms associated with the MV and MM cases are similar to VV cases but show increasing levels of proteaseresistance; 3) abnormal tau is present in all three genotypic forms of PSPr with features apparently similar to those of primary tauopathies placing PSPr at the intersection of tauopathies and prion diseases.
Discussion: Will focus on: 1) the features of the abnormal PrP in the newly discovered 129MV and 129MM PSPr; 2) the effect of the 129 polymorphism on PSPr compared to that on sCJD; 3) the relationship of PSPr with tauopathies; 4) whether PSPr now with the three 129 genotypic forms is the long sought sporadic form of GSS.
(Supported by NIH AG-14359, NS052319, CDC UR8/CCU515004).
Ann Neurol. 2010 Aug;68(2):162-72.
Variably protease-sensitive prionopathy: a new sporadic disease of the prion protein.
Zou WQ, Puoti G, Xiao X, Yuan J, Qing L, Cali I, Shimoji M, Langeveld JP, Castellani R, Notari S, Crain B, Schmidt RE, Geschwind M, Dearmond SJ, Cairns NJ, Dickson D, Honig L, Torres JM, Mastrianni J, Capellari S, Giaccone G, Belay ED, Schonberger LB, Cohen M, Perry G, Kong Q, Parchi P, Tagliavini F, Gambetti P.
Department of Pathology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH 44106, USA.
wenquan.zou@case.edu
Abstract OBJECTIVE: The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV).
METHODS: Fifteen affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics.
RESULTS: Disease duration (between 22 and 45 months) was significantly different in the 129VV and 129MV subjects. Most other phenotypic features along with the PrP electrophoretic profile were similar but distinguishable in the 3 129 genotypes. A major difference laid in the sensitivity to protease digestion of the disease-associated PrP, which was high in 129VV but much lower, or altogether lacking, in 129MV and 129MM. This difference prompted the substitution of the original designation with "variably protease-sensitive prionopathy" (VPSPr). None of the subjects had mutations in the PrP gene coding region.
INTERPRETATION: Because all 3 129 genotypes are involved, and are associated with distinguishable phenotypes, VPSPr becomes the second sporadic prion protein disease with this feature after Creutzfeldt-Jakob disease, originally reported in 1920. However, the characteristics of the abnormal prion protein suggest that VPSPr is different from typical prion diseases, and perhaps more akin to subtypes of Gerstmann-Sträussler-Scheinker disease.
PMID: 20695009 [PubMed - indexed for MEDLINE]
None of the subjects had mutations in the PrP gene coding region....???...TSS
iatrogenic, what if?
Saturday, April 9, 2022
EFSA EU Request for a scientific opinion on the monitoring of Chronic Wasting Disease (CWD) EFSA-Q-2022-00114 M-2022-00040 Singeltary Submission
WEDNESDAY, APRIL 13, 2022
UT Health Soto receives $13 million NIH grant to further research on chronic wasting disease
Terry S. Singeltary Sr.
