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Ahead of Print -Variably Protease-Sensitive Prionopathy, a Unique Prion Variant with Inefficient Transmission Properties - Volume 20, Number 12—December 2014 - Emerging Infectious Disease journal - CDC

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Ahead of Print -Variably Protease-Sensitive Prionopathy, a Unique Prion Variant with Inefficient Transmission Properties - Volume 20, Number 12—December 2014 - Emerging Infectious Disease journal - CDC

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Volume 20, Number 12—December 2014


Variably Protease-Sensitive Prionopathy, a Unique Prion Variant with Inefficient Transmission Properties

Abigail B. Diack1, Diane L. Ritchie1, Alexander H. Peden, Deborah Brown, Aileen Boyle, Laura Morabito, David Maclennan, Paul Burgoyne, Casper Jansen, Richard S. Knight, Pedro Piccardo, James W. Ironside1, and Jean C. Manson1Comments to Author 
Author affiliations: The Roslin Institute, University of Edinburgh, Easter Bush, Scotland, UK (A.B. Diack, D. Brown, A, Boyle, L. Morabito, D. Maclennan, P. Burgoyne, J.C. Manson)School of Clinical Sciences, University of Edinburgh, Edinburgh, Scotland, UK (D.L. Ritchie, A.H. Peden, R.S. Knight, J.W. Ironside)Food and Drug Administration, Rockville, Maryland, USA (P. Piccardo)University Medical Centre Utrecht, Utrecht, the Netherlands (C. Jansen)


Variably protease-sensitive prionopathy (VPSPr) can occur in persons of all codon 129 genotypes in the human prion protein gene (PRNP) and is characterized by a unique biochemical profile when compared with other human prion diseases. We investigated transmission properties of VPSPr by inoculating transgenic mice expressing human PRNP with brain tissue from 2 persons with the valine-homozygous (VV) and 1 with the heterozygous methionine/valine codon 129 genotype. No clinical signs or vacuolar pathology were observed in any inoculated mice. Small deposits of prion protein accumulated in the brains of inoculated mice after challenge with brain material from VV VPSPr patients. Some of these deposits resembled microplaques that occur in the brains of VPSPr patients. Comparison of these transmission properties with those of sporadic Creutzfeldt-Jakob disease in the same lines of mice indicated that VPSPr has distinct biological properties. Moreover, we established that VPSPr has limited potential for human-to-human transmission.
Human prion diseases, also called transmissible spongiform encephalopathies, are a group of rare and inevitably fatal neurodegenerative diseases. Prion diseases are unique in that they occur as idiopathic (sporadic), familial, and acquired disorders. The sporadic form of Creutzfeldt-Jakob disease (sCJD) accounts for >80% of all human prion diseases. Six subtypes of sCJD have been classified according to the prion protein (PrP) genotype at codon 129 (methionine [M]/M, M/valine [V], VV) and the biochemical profile of the protease-resistant core of the abnormal disease-specific PrP (PrPres) (PrPres type 1 or PrPres type 2A or 2B) (1,2). Experimental transmission of brain tissue from patients of these 6 different sCJD subtypes into 3 transgenic mouse lines expressing different human prion protein gene PRNP sequences (coding for 129MM, MV, and VV) has identified 4 distinct strains of the CJD agent (3).
In 2008, a novel prion disease, initially referred to as protease-sensitive prionopathy, was reported in 11 patients who had been referred to the National Prion Disease Pathology Surveillance Center (Cleveland, OH, USA) during May 2002–January 2006. All 11 patients were of the PRNP codon 129VV genotype, and postmortem examination of brain tissues showed that the patients had a spongiform encephalopathy (4). As with patients with sCJD, these patients had no mutations in the PRNP coding region, and no risk factors for the development of iatrogenic CJD were identified among the patients. The defining feature of this group of patients was the unusual biochemical properties of the abnormal PrP in the brain. Compared with the biochemical properties of PrPres in sCJD, the PrPres in VPSPr was found to be much less resistant to protease digestion. VPSPr PrPres shows a faint ladder-like appearance of protease-resistant fragments on Western blot and a prominent low–molecular weight fragment of ≈8 kDa. The neuropathologic features in this group were also unusual, in particular, the accumulation of microplaques within the cerebellum and thalamus, which stained intensely for PrP.
Since the original description of those 11 cases, 19 additional cases have been reported, including some in patients of the PRNP codon 129MM and 129MV genotypes (57). Although case numbers remain low, the prevalence of this novel prion disease appears to vary according to the codon 129 genotype of affected persons: 62% of reported cases have been detected in persons of the PRNP codon 129VV genotype. In comparison, 17% of sCJD cases and only 12% of the general white population are of the PRNP codon 129VV genotype (8,9). Subsequent studies showed differences between the 3 codon 129 genotypes in protease digestion sensitivity of the abnormal PrP in the brain. This difference in protease sensitivity has resulted in the condition being renamed variably protease-sensitive prionopathy (VPSPr) (10).
The presence of PrPres in VPSPr suggests that PrP plays a central role in the disease process. However, the relationship between different forms of PrP and prion disease has not been established. It is possible that the protease-sensitive and the truncated forms of the abnormal PrP may contribute to the unique neuropathology of VPSPr and may also influence the potential for transmission of disease to other persons.
Human-to-human transmission of prion diseases is of great concern for public health reasons (1113). The use of gene-targeted transgenic mice expressing human PrP enables the direct comparison of transmission properties by using well-defined strains of sCJD and variant CJD (vCJD). Moreover, this system enables the prediction of disease transmission between persons and has been used extensively to predict the potential for human-to-human spread of sCJD and vCJD (3,1416). In this study, we challenged human PrP–expressing transgenic mice with brain tissue from 3 persons with VPSPr and directly compared the data with those from previous sCJD transmission experiments in these mouse lines. Thus, we determined whether any biological similarities exist between these apparently different prion diseases. Furthermore, these transmissions enabled an assessment of the potential for human-to-human transmission of VPSPr.

Dr Diack is a research fellow at The Roslin Institute, University of Edinburgh. Her research interests focus on prion diseases, in particular, strain characterization and modeling of human diseases.


We thank the animal facility staff of the Neurobiology Division, The Roslin Institute for animal care and clinical scoring; the pathology staff of The Roslin Institute for sectioning the mouse brains and assessing levels of transmissible spongiform encephalopathy vacuolation; Dorothy Kisielewski for technical support; Mark Head for advice on the biochemistry of VPSPr; Annemieke Rozemuller for collaboration and neuropathologic expertise; and Jan Langeveld for providing the 1E4 antibody.
The Edinburgh Brain Bank, a source of material for this study, is supported by the Medical Research Council (MR/L016400/1). This report is independent research commissioned and funded by the Department of Health Policy Research Programme (Strain typing and investigation of transmission potential of unusual cases of CJD).


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Suggested citation for this article: Diack AB, Ritchie DL, Peden AH, Brown D, Boyle A, Morabito L, et al. Variably protease-sensitive prionopathy, a unique prion variant with inefficient transmission properties. Emerg Infect Dis. 2014 Dec [date cited]. http://dx.doi.org/10.3201/eid2012.140214
DOI: 10.3201/eid2012.140214
1These authors contributed equally to this work.

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