Variably Protease-Sensitive Prionopathy: a Novel Disease of the Prion Protein

J Mol Neurosci (2011) 45:422424 DOI 10.1007/s12031-011-9543-1

Variably Protease-Sensitive Prionopathy: a Novel Disease of the Prion Protein

Pierluigi Gambetti & Gianfranco Puoti & Wen-Quan Zou

Received: 15 April 2011 /Accepted: 3 May 2011 /Published online: 17 May 2011 # Springer Science+Business Media, LLC 2011

Abstract Variably protease-sensitive prionopathy (VPSPr) is a novel disease involving the prion protein (PrP) that has clinical similarities with non-Alzheimers dementias especially frontotemporal dementia, diffuse Lewis body disease, and normal pressure hydrocephalus. VPSPr can be distinguished from sporadic CreutzfeldtJakob disease (sCJD) especially for the characteristics of the abnormal PrP. Furthermore, although VPSPr like sCJD affects patients with the three PrP genotypes as determined by the common methionine/valine polymorphism, the allelic prevalence is very different in the two diseases. These findings suggest that VPSPr is basically different from classical prion diseases such as sCJD being perhaps more akin to other neurodegenerative dementias.

Keywords Variably protease-sensitive prionopathy.

Prions . Prion protein . Prion diseases . CreutzfeldtJakob disease . Alzheimers disease

Introduction

In 2008, we reported 11 cases affected by a disease that differed from typical human prion diseases such as sporadic and familial CreutzfeldtJakob disease (CJD) clinically,

pathologically, and more importantly for the characteristics of the abnormal, disease-related prion protein (PrPDis)

present in the brain of these cases (Gambetti et al. 2008). A striking feature of the PrPDis was the apparent lack of resistance to treatment with proteases as opposed to the protease resistance that is a prominent feature of typical prion diseases. Another striking feature of these cases was the genotype of the prion protein (PrP) gene which is characterized by a common methionine (Met)/valine (Val) polymorphism at codon 129 (Collinge et al. 1991). All the 11 cases were homozygous for Val at codon 129 of the PrP gene although the prevalence of this PrP genotype in the general Caucasian population is approximately 12% (Collinge et al. 1991). Furthermore, none of the cases had a mutation in the open reading frame (ORF) of the PrP gene where all the known mutations have been found (Kong et al. 2004) although six of the ten informative cases had family history of dementia.

In 2010, we reported 15 new cases affected by a condition similar to that previously described for clinical and histopathological features as...