A novel human disease with abnormal prion protein sensitive to protease

Human prion diseases or transmissible spongiform encephalopathies may be sporadic, inherited or acquired by infection. 1 Creutzfeldt-Jakob disease (CJD) is the most common phenotype and occurs in all three forms. In the sporadic form, CJD is classified into five subtypes, which can be readily distinguished based on clinical features, type and distribution of brain lesions, and pattern of prion protein (PrP) immunostaining. 2, 3 Fatal insomnia (FI), a much rarer phenotype, includes sporadic and inherited forms and is characterized by loss of ability to sleep and preferential thalamic degeneration. 4 Gerstmann-Straussler-Scheinker disease (GSS), the third phenotype, occurs exclusively as a heritable disease invariably associated with a mutation in the PrP gene open reading frame (ORF) and is characterized by the presence of prion amyloid plaques. 4 In spite of their heterogeneity, all sporadic human prion diseases described to date have been associated with abnormal PrP (commonly called PrPSc but henceforth referred to as PrPr ), which is resistant to treatment with proteases and is considered the diagnostic hallmark of these diseases. 1 PrPr is derived from normal or cellular PrP (PrPC) via a post-translational transition from α-helical-to β-sheet-rich conformations. PrPC and PrPr are quite different. While PrPC is soluble in non-denaturing detergents and is completely digested when exposed to appropriate concentrations of proteinase K (PK), PrPr is detergent insoluble and its C-terminal region resists PK-treatment. 5 Based on the size of their PK-resistant fragments, at least three major PrPr types are recognized, which co-distribute with specific disease phenotypes: i) PrPr type 1, which upon PK-treatment generates a ~21 kilo Daltons (kDa) fragment; ii) PrPr type 2, generating a ~19 kDa fragment; and iii) PrP7-8, a PrP internal fragment of 7–8 kDa. 4–6 Both PrPr types 1 and 2 have been observed associated with distinct subtypes of CJD. To date, PrP7-8 has been consistently observed only in GSS. Therefore, the conformational changes, which render PrPr pathogenic and in many, but not in all cases, infectious, may engender different species or strains of PrPr that can be recognized based on their distinct protease-resistant fragments and by their associated clinical-pathological phenotype. 5, 7–12 Studies mostly based on experimental models, have recently shown that PK-resistant PrP (PrPr) is associated with varying quantities of a PrP isoform that, as PrPr, is detergent-insoluble but sensitive to protease digestion (PrPs).11–15 The relationship of PrPs with PrPr and the role that PrPs plays in the pathogenesis of prion diseases remains uncertain. 16–18 Here we report eleven subjects with a human disease characterized by the presence of detergent insoluble PrP that is predominantly sensitive to protease digestion and forms unusual immunohistochemical patterns. Furthermore, the small amount of PrPr present generates a distinct profile on immunoblot. Several affected subjects have family history of dementia but lack mutations in the PrP gene ORF. We refer to this condition as protease-sensitive prionopathy (PSPr). PSPr broadens the spectrum of human prion diseases and raises several important issues related to the very nature of these diseases when they are associated with different PrP isoforms. Among prion diseases PSPr is not very rare. Since the presenting clinical signs often suggest the diagnosis of non-Alzheimer dementia, PSPr might be even more prevalent than our data indicate because many PSPr cases might currently be classified within this group of dementias. Parts of this study have been previously presented. 19