Atypical Creutzfeldt-Jakob disease with PrP-amyloid plaques in white matter: molecular characterization and transmission to bank voles show the M1 strain signature

Marcello Rossi,Michele Di Bari,Annemieke Rozemuller,Laura Pirisinu,Piero Parchi,Simone Baiardi,Afina Willemina Lemstra,Daniela Saverioni,Romolo Nonno,Sabina Capellari

doi:10.1186/s40478-017-0496-7

Abstract

Amyloid plaques formed by abnormal prion protein (PrPSc) aggregates occur with low frequency in Creutzfeldt-Jakob disease, but represent a pathological hallmark of three relatively rare disease histotypes, namely variant CJD, sporadic CJDMV2K (methionine/valine at PRNP codon 129, PrPSc type 2 and kuru-type amyloid plaques) and iatrogenic CJDMMiK (MM at codon 129, PrPSc of intermediate type and kuru plaques). According to recent studies, however, PrP-amyloid plaques involving the subcortical and deep nuclei white matter may also rarely occur in CJDMM1 (MM at codon 129 and PrPSc type 1), the most common CJD histotype.To further characterize the phenotype of atypical CJDMM1 with white matter plaques (p-CJDMM1) and unravel the basis of amyloid plaque formation in such cases, we compared clinical and histopathological features and PrPSc physico-chemical properties between 5 p-CJDMM1 and 8 typical CJDMM1 brains lacking plaques. Furthermore, transmission properties after bioassay in two genetic lines of bank voles were also explored in the two groups.All 5 p-CJDMM1 cases had a disease duration longer than one year. Three cases were classified as sporadic CJDMM1, one as sporadic CJDMM1 + 2C and one as genetic CJDE200K-MM1. Molecular mass, protease sensitivity and thermo-solubilization of PrPSc aggregates did not differ between p-CJDMM1 and classical CJDMM1 cases. Likewise, transmission properties such as incubation time, lesion profile and PrPSc properties in bank voles also matched in the two groups.The present data further define the clinical-pathologic phenotype of p-CJDMM1, definitely establish it as a distinctive CJD histotype and demonstrate that PrP-plaque formation in this histotype is not a strain-specific feature. Since cases lacking amyloid plaques may also manifest a prolonged (i.e. > than one year) disease course, unidentified, host-specific factors likely play a significant role, in addition to disease duration, in generating white matter PrP-amyloid plaques in p-CJDMM1.

Highlights

Prion diseases are a group of neurodegenerative disorders of humans and other mammals characterized by misfolding of the cellular prion protein (PrPC)
Patients and tissues We studied 5 subjects affected by CJDMM1 associated with Scrapie prion protein (PrPSc) plaque-type deposits in white matter and 8 cases affected by typical CJDMM1
The present study further establishes the existence of a rare CJD subtype, occurring in approximately 0.5% of CJD cases, designated as p-CJDMM1

Summary

Introduction

Prion diseases are a group of neurodegenerative disorders of humans and other mammals characterized by misfolding of the cellular prion protein (PrPC). Sporadic Creutzfeldt-Jakob disease (sCJD), the most common prion disease in humans, can be classified into 6 major phenotypic variants, according to molecular, histopathological, and clinical features [21, 24, 25]. These variants or histotypes largely correlate at molecular level with the genotype at the polymorphic PRNP codon 129, encoding for methionine (M) or valine (V), and the relative molecular mass of PrPSc core fragment generated after proteolytic digestion, which can be 21 (type 1) or 19 kDa (type 2) [22]. Other physico-chemical properties distinguishing PrPSc aggregates among sCJD variants, associated with either type 1 or type 2, include the relative amount of the truncated C-terminal fragments, named CTF12–13 based on their molecular mass, and the socalled glycoform ratio, that is the ratio among the three differently glycosylated (e.g. di-, mono-, and unglycosylated) PrPSc forms [20, 22, 32]

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