We report eleven patients affected by a disease that involves abnormal PrP and has homogeneous and distinctive features (). Based on several lines of evidence we argue that these features allow for the separation of this condition from all known forms of human prion disease. Firstly, the abnormal PrP associated with this disease is predominantly – and in several brain regions almost exclusively – sensitive to protease or PrPs, and the PK-resistant PrP isoform or PrPr has a very distinctive electrophoretic profile. The high sensitivity to PK and the distinctive electrophoretic profile of the abnormal PrP clearly distinguish the present cases from each of the five subtypes of sCJD and from sFI, the known human sporadic prion diseases. 1
For example, compared to sCJDMM1, the most common and typical sCJD, 2
the present cases have 16-times less total abnormal PrP, and the fraction of the total abnormal PrP that is PK-resistant is nearly 4-times less. Furthermore, the ladder-like electrophoretic profile of the PrPr associated with this condition has not been observed in either sCJD or sFI, all of which instead are characterized by the presence of the well known PrPr type 1 or type 2. 1
When present, the traditional PrPr, commonly called PrP27-30, was located in sub-cortical regions and was of type 1 another combination not observed in sporadic human prion diseases. 1
Secondly, the present cases are also homogeneous as for the PrP coding genotype since they are all homozygous for valine at codon 129 of the PrP gene, the site of a common methionine/valine polymorphism.28
Valine homozygosity in Caucasians is the rarest 129 genotype being found only in 12% of the population. 28
The sCJD subtypes associated with valine homozygosity, sCJDVV1 and sCJDVV2, have been well characterized and differ from the present cases phenotypically and for the characteristics of the abnormal PrP. 1
Thirdly, the pattern of PrP immunostaining and the presence of structures with the features of poorly formed plaques that we observed in the cerebellum are to our knowledge unprecedented. Lastly, the clinical presentation and initial course that prominently features relatively slow cognitive deterioration, occasional gait impairment and incontinence has evoked the diagnoses of normal pressure hydrocephalus, diffuse Lewy body disease or frontotemporal dementia while prion disease was only suspected at a later stage based on the relatively short duration.
Summary of PSPr common features
Although the present cases can be easily distinguished from sporadic prion diseases, some of their features such as overrepresentation of PrPs and the multiple PK-resistant PrP fragments have been reported in GSS. 4
However, all cases of GSS reported to date are associated with a mutation in the coding region of the PrP gene or immediately adjacent to it. 4
None of the present cases carried such mutation. Moreover, the ladder-like PK-resistant PrP fragments observed in our cases are preferentially detected with 1E4 but not with 3F4, which obviously separates the present cases from GSS carrying the multiple PK-resistant PrP fragments. In a recent study we observed that although 1E4 and 3F4 have adjacent epitopes along human PrP residues 97–112, their accessibility to these epitopes is different due to different neighboring N-terminal residues. 29
It is possible that the 1E4-selectively detected PK-resistant PrP fragments may have N-terminal starting sites that are different from those of the well-characterized PrPr type 1 and 2. The above evidence clearly indicates that the present condition differs from GSS although the possibility that it represents the long sought sporadic form of GSS remains to be excluded. Six of the ten subjects with obtainable pedigree had a family history of dementia that cannot be ignored, yet none carried a mutation in the PrP gene ORF. Therefore, at least in some cases a causative mutation might be located outside the ORF of the PrP gene, a condition never observed in human prion diseases. 1
All these considerations argue that the eleven patients were affected by a novel condition involving the PrP that cannot be classified within the spectrum of currently known human prion diseases. We suggest the designation of protease-sensitive prionopathy or PSPr to emphasize a major distinctive feature ().
Compared with other human prion diseases, PSPr is not exceedingly rare, as it accounts for about 3% of all sCJD and 16% of all valine homozygous CJD accessioned by the NPDPSC during the same time period as these eleven subjects, making PSPr about as common as some of the well known sporadic prion diseases (such as sCJDMM2, sFI and sCJDVV1). 2
Furthermore, since the clinical presentation and the duration of PSPr often do not point to the diagnosis of prion disease, some cases of PSPr might currently be classified within the group of non-Alzheimer’s dementias and not be investigated further. Should this be the case, PSPr might be more common than the present study suggests.
The small amount of PrPr associated with PSPr and the finding that about 76% of the detectable abnormal PrP is PK-sensitive not only hinders the diagnosis but also has implications concerning origin, pathogenicity, infectivity and classification of PSPr.
The discovery of PrPs has opened a new chapter in prion diseases.11–15
The demonstration that PrPs forms smaller aggregates than the PrPr counterpart 16
and that it is competent to convert PrPC
to PrPr in vitro
, as well as to seed the polymerization of recombinant PrP into amyloid 17, 18
suggests that PrPs shares defining features with PrPr. However, the pathogenetic mechanisms of PrPs in the absence of PrPr and, therefore, the very nature of the prion diseases associate with PrPs currently remain conjectural.
Prion diseases associated with PrPs, in the presence of minimal or no PrPr, have been modeled and studied in detail in a variety of transgenic (Tg) mouse lines carrying mouse homologues of human PrP gene mutants or over-expressing PrPC
. 12, 30–33
Two Tg mouse models appear relevant to the present cases.
In the first model, Tg mice expressing high levels of mouse PrP carrying the P101L mutation, the mouse equivalent of the human P102L mutation associated with a GSS phenotype, 4, 34, 35
spontaneously developed a neurodegenerative process characterized by spongiform degeneration and prion plaque formation. Following inoculation, they transmitted a disease phenotypically similar to P101L mutated Tg mice but not to wild type mice. As in the present cases, the affected mice had PrPs but no, or minimal amounts of, PrPr indicating that PrPs can be associated with a prion disease that is partially transmissible and has a histopathological phenotype displaying general features of prion diseases. 12
In the second model, Tg mice carrying the P101L mutation were inoculated with brain homogenate from patients affected by a subtype of GSS P102L characterized by the exclusive presence of a ~8 kDa PK-resistant fragment reminiscent of the ~6 kDa fragment observed in small amount in our cases. The inoculated Tg mice remained largely asymptomatic but at histological examination they displayed PrP plaques and had minimal amounts of PrPr. 33
They failed to transmit the disease to wild-type mice but inoculation to P101L mutated mice resulted in the formation of PrP plaques in the absence of clinical disease.
These mouse models and now the present cases raise issues with the definition of prion diseases. Currently, it is unclear whether PSPr is transmissible because time-consuming transmissibility experiments to different lines of Tg mice and in vitro
PrP replication are still ongoing. Should PSPr not be transmissible, the question is whether or not it is a prion disease. A similar question can be raised for GSS of which to date only one subtype has been shown to be consistently transmissible.4
The issue is further compounded by the recent evidence that amyloid β, the pathogenic peptide of Alzheimer’s disease (AD) has the propensity to replicate following inoculation into susceptible Tg mice in a conformation-dependent fashion reminiscent of prions.36
These findings seem to blur the once tight association of prion diseases and transmissibility. It may be more practical to apply the label of prion diseases to all conditions in which the prion protein is abnormal and appears to play a central role in the pathology, as in all prion diseases known to date and in PSPr. 37
In contrast, one might reserve the qualification of transmissible to those prion diseases that can be transmitted to recipients expressing relatively normal amounts of wild type PrP. 36
The finding that several PSPr patients had first degree relatives diagnosed with dementia necessitates a search for an underlying genetic cause. In AD, the discovery of mutations outside the gene of the amyloid precursor protein (the central protein in AD, as PrP is in prion diseases) has provided a wealth of information regarding pathogenetic mechanisms of AD. 38
Similarly, the discovery of a mutation outside the PrP gene ORF capable of generating a prion disease might greatly expand our understanding of pathogenetic mechanisms and the role of PrP in prion diseases.