Creutzfeldt‐Jakob disease profile in patients homozygous for the PRNP E200K mutation

Abstract

We identified 70 Creutzfeldt-Jakob disease patients with the previously described E200K mutation in the prion protein gene. The purpose of this study was to define the clinical features of E200K homozygous patients (n = 5), compared with heterozygotes. We found a statistically significant younger age at disease onset for the homozygous patients, although the average age at onset in this group was still in midlife. Disease features were not statistically different in the two groups. Possible explanations are discussed.

An insight of early PrP‐E200K aggregation by combined molecular dynamics/fragment molecular orbital approaches

“…Recently, we have investigated the molecular interaction properties of either wild type or E200K‐mutated PrP C by the use of multilayered computational procedures . E200K is a well‐characterized pathogenic mutation associated to a familial or genetic form of CJD . A model of PrP‐E200K dimer, formed by the assembly of two 120‐231 segments of PrP‐E200K, has been built through the identification of two protein portions region 1 and region 3, in which we have detected a peculiar electrostatic complementarity, negatively and positively charged, respectively .…”

“…All these proteins are physiologically expressed in the body and, normally, are all subjected to homeostatic mechanisms that control their metabolism and activity, such as protease degradation, and hamper their detrimental accumulation and/or degradation into damaging aggregates . On the other hand, several mutants of these proteins have been identified to manifest a high pathogenic potential prompted by either an incorrect metabolism or by an intrinsically higher propensity to form aggregates, giving rise to inheritable or familial form of neurodegenerative diseases . A common feature of the above‐mentioned pathologies is the formation of prion particles that are: (1) protease‐resistant with a high content of cross‐β domains, (2) fibrillar assembly, (3) capable of promoting the conversion of naturally expressed monomers presumably into aggregation‐prone conformation via a template‐based mechanism (infectivity).…”

“…Recently, we have investigated the molecular similarity in PrP protein systems through the development of computational techniques . In spite of the almost superimposable tertiary structures, wild type and the pathogenic E200K mutant disclosed appreciable differences in the pattern of surface charges that could explain the higher aggregation propensity of the mutated protein . The formation of early—though still non scrapie—aggregates of E200K‐PrP C may represent a first step in the prion pathogenesis and may have a triggering effect on the scrapie formation.…”

Coexpression of Wild‐type and Mutant Prion Proteins Alters Their Cellular Localization and Partitioning into Detergent‐resistant Membranes

“…For example, inheritable human prion diseases such as fCJD and GSS have been studied now for almost a century (the first case being described by Hans‐Gerhard Creutzfeldt in 1920), while the mechanisms of pathogenesis remain enigmatic. The aim of this work was to simulate in a cell culture system the heterozygous situation found in the majority of patients with inheritable TSE diseases (30,45,46). Thus, both PrPwt and PrPmut were expressed in the same cell, to analyse whether and how each of the two proteins affected the biochemistry as well as the cellular and subcellular localization of each other.…”

“…Another notable characteristic of the familial TSE diseases that has been somewhat neglected is the fact that the majority of patients are heterozygous for the mutations of the prnp gene (30). We were interested in characterizing this clinically relevant situation of heritable prion disease by mimicking heterozygosis in a cell culture model to examine the phenotypic effect of the heterozygous genotype at the subcellular and biochemical level.…”