Glycoform-selective prion formation in sporadic and familial forms of prion disease

The four glycoforms of the cellular prion protein (PrP(C)) variably glycosylated at the two N-linked glycosylation sites are converted into their pathological forms (PrP(Sc)) in most cases of sporadic prion diseases. However, a prominent molecular characteristic of PrP(Sc) in the recently identified variably protease-sensitive prionopathy (VPSPr) is the absence of a diglycosylated form, also notable in familial Creutzfeldt-Jakob disease (fCJD), which is linked to mutations in PrP either from Val to Ile at residue 180 (fCJD(V180I)) or from Thr to Ala at residue 183 (fCJD(T183A)). Here we report that fCJD(V180I), but not fCJD(T183A), exhibits a proteinase K (PK)-resistant PrP (PrP(res)) that is markedly similar to that observed in VPSPr, which exhibits a five-step ladder-like electrophoretic profile, a molecular hallmark of VPSPr. Remarkably, the absence of the diglycosylated PrP(res) species in both fCJD(V180I) and VPSPr is likewise attributable to the absence of PrP(res) glycosylated at the first N-linked glycosylation site at residue 181, as in fCJD(T183A). In contrast to fCJD(T183A), both VPSPr and fCJD(V180I) exhibit glycosylation at residue 181 on di- and monoglycosylated (mono181) PrP prior to PK-treatment. Furthermore, PrP(V180I) with a typical glycoform profile from cultured cells generates detectable PrP(res) that also contains the diglycosylated PrP in addition to mono- and unglycosylated forms upon PK-treatment. Taken together, our current in vivo and in vitro studies indicate that sporadic VPSPr and familial CJD(V180I) share a unique glycoform-selective prion formation pathway in which the conversion of diglycosylated and mono181 PrP(C) to PrP(Sc) is inhibited, probably by a dominant-negative effect, or by other co-factors

Potential human transmission of amyloid β pathology: surveillance and risks

Studies in experimental animals show transmissibility of amyloidogenic proteins associated with prion diseases, Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Although these data raise potential concerns for public health, convincing evidence for human iatrogenic transmission only exists for prions and amyloid β after systemic injections of contaminated growth hormone extracts or dura mater grafts derived from cadavers. Even though these procedures are now obsolete, some reports raise the possibility of iatrogenic transmission of amyloid β through putatively contaminated neurosurgical equipment. Iatrogenic transmission of amyloid β might lead to amyloid deposition in the brain parenchyma and blood vessel walls, potentially resulting in cerebral amyloid angiopathy after several decades. Cerebral amyloid angiopathy can cause life-threatening brain haemorrhages; yet, there is no proof that the transmission of amyloid β can also lead to Alzheimer's dementia. Large, long-term epidemiological studies and sensitive, cost-efficient tools to detect amyloid are needed to better understand any potential routes of amyloid β transmission and to clarify whether other similar proteopathic seeds, such as tau or α-synuclein, can also be transferred iatrogenically

Regulating Factors of PrPres Glycosylation in Creutzfeldt-Jakob Disease - Implications for the Dissemination and the Diagnosis of Human Prion Strains

OBJECTIVE: The glycoprofile of pathological prion protein (PrP(res)) is widely used as a diagnosis marker in Creutzfeldt-Jakob disease (CJD) and is thought to vary in a strain-specific manner. However, that the same glycoprofile of PrP(res) always accumulates in the whole brain of one individual has been questioned. We aimed to determine whether and how PrP(res) glycosylation is regulated in the brain of patients with sporadic and variant Creutzfeldt-Jakob disease. METHODS: PrP(res) glycoprofiles in four brain regions from 134 patients with sporadic or variant CJD were analyzed as a function of the genotype at codon 129 of PRNP and the Western blot type of PrP(res). RESULTS: The regional distribution of PrP(res) glycoforms within one individual was heterogeneous in sporadic but not in variant CJD. PrP(res) glycoforms ratio significantly correlated with the genotype at codon 129 of the prion protein gene and the Western blot type of PrP(res) in a region-specific manner. In some cases of sCJD, the glycoprofile of thalamic PrP(res) was undistinguishable from that observed in variant CJD. INTERPRETATION: Regulations leading to variations of PrP(res) pattern between brain regions in sCJD patients, involving host genotype and Western blot type of PrP(res) may contribute to the specific brain targeting of prion strains and have direct implications for the diagnosis of the different forms of CJD

A genome wide association study links glutamate receptor pathway to Sporadic Creutzfeldt-Jakob disease risk.

We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 control

De certaines différences entre le français et l'anglais

Kayne Richard S., Haïk Isabelle. De certaines différences entre le français et l'anglais. In: Langages, 14ᵉ année, n°60, 1980. Syntaxe générative et syntaxe comparée, sous la direction de Alain Rouveret. pp. 47-64

La maladie de Parkinson est-elle une maladie à prion ?

National audienceThe accumulation of a specific protein in aggregated form is a common phenomenon in human neurodegenerative diseases. In Parkinson's disease, this protein is α-synuclein which is a neuronal protein of 143 amino acids. With a monomeric conformation in solution, it also has a natural capacity to aggregate into amyloid structures (dimers, oligomers, fibrils and Lewy bodies or neurites). It therefore fulfils the characteristics of a prion protein (different conformations, seeding and spreading). In vitro and in vivo experimental evidence in transgenic and wild animals indicates a prion-like propagation of Parkinson's disease. The sequential and predictive distribution of α-synuclein demonstrated by Braak et al. and its correlation with non-motor signs are consistent with the prion-like progression. Although the triggering factor causing the misfolding and aggregation of the target protein is unknown, Parkinson's disease is a highly relevant model for the study of these mechanisms and also to test specific treatments targeting the assemblies of α-synuclein and propagation from pre-motor phase of the disease. Despite this prion-like progression, there is currently no argument indicating a risk of human transmission of Parkinson's disease.L'accumulation d'une protéine spécifique sous forme agrégée est un phénomène commun aux maladies neurodégénératives humaines. Dans la maladie de Parkinson, cette protéine est l'α-synucléine qui est une protéine neuronale de 143 acides aminés. De conformation monomérique en solution, elle possède également une capacité naturelle à s'agréger en structures amyloïdes (dimères, oligomères, fibrilles puis corps ou neurites de Lewy). Elle détient donc les caractéristiques d'une protéine prion (différentes conformations, initiation et dissémination d'un processus transconformationnel). De nombreux arguments expérimentaux in vitro et in vivo sur des animaux transgéniques ou sauvages sont en faveur d'une progression prion-like de la maladie de Parkinson. La diffusion séquentielle et prédictive de l'α-synucléine mise en évidence par Braak et al. et sa corrélation avec les signes non moteurs vont tout à fait dans le sens de cette progression prion-like. Même si le facteur déclenchant à l'origine du mauvais repliement et de l'agrégation de la protéine cible reste inconnu, la maladie de Parkinson est un modèle très pertinent pour l'étude de ces mécanismes et aussi pour tester des traitements spécifiques ciblant les assemblages d'α-synucléine et leur propagation dès la phase pré-motrice de la maladie. Malgré cette progression prion-like, il n'existe actuellement aucun argument indiquant un risque de transmission interhumaine de la maladie de Parkinson

Sporadic Creutzfeldt-Jakob disease mimicking nonconvulsive status epilepticus.

International audienceBACKGROUND: Nonconvulsive status epilepticus (NCSE) in patients with confusion may be difficult to distinguish from nonepileptic (metabolic/toxic, postanoxic, and spongiform) encephalopathies. This study aimed to describe the misleading presentation of patients with sporadic Creutzfeldt-Jakob disease (sCJD) who were initially diagnosed with a refractory NCSE (rNCSE). METHODS: We retrospectively reviewed the clinical characteristics, EEG records, brain MRI scans, 14-3-3 protein detection in CSF, genotype of the prion protein gene, and neuropathologic data of patients referred to our neurologic intensive care unit (NICU) with this presentation. RESULTS: Ten patients with a final diagnosis of definite (n = 7) or probable (n = 3) sCJD were referred to our NICU with an initial diagnosis of rNCSE. Reanalysis of the EEG ruled out ictal rhythmic activities, but showed diffuse, periodic, or semiperiodic sharp-wave complexes (PSWC) with short period. PSWC were briefly attenuated by auditory (n = 5) or painful (n = 3) stimuli and by IV injection of antiepileptic drugs (n = 5) but without clinical improvement. In addition, PSWC showed fluctuations according to the vigilance level (n = 5). Brain MRI showed hyperintensities in basal ganglia (n = 9/10) and in cortical areas (n = 7/10). 14-3-3 Protein was detected in CSF (n = 10). Only 2 sCJD subtypes were found (MM1 5/7, MV1 2/7). CONCLUSIONS: This series of patients suggests that sporadic Creutzfeldt-Jakob disease should be considered as a differential diagnosis, rather than as a cause, of apparent refractory nonconvulsive status epilepticus. Criteria for nonconvulsive status epilepticus diagnosis should rely on careful examination of both EEG parameters and clinical state so that aggressive, unnecessary treatments can be avoided

Erratum: Can Mortality Data Provide Reliable Indicators for Creutzfeldt-Jakob Disease Surveillance? A Study in France from 2000 to 2008

<i>Background:</i> Surveillance of Creutzfeldt-Jakob disease (CJD) is still an important issue because of the variant CJD epidemic, which is in decline and also because of the emergence of novel forms of animal transmissible spongiform encephalopathy with zoonotic potential and the risk of nosocomial and blood transfusion-related transmission. Active surveillance has been implemented in most European countries and requires important human resources and funding. Here, we studied whether national mortality and morbidity statistics can be used as reliable indicators. <i>Methods:</i> CJD data collected by the French national CJD surveillance centre were compared with data registered in the national mortality statistics. <i>Results:</i> From 2000 to 2008, the two sources reported fairly similar numbers of CJD deaths. However, analysis of individual data showed important between-sources disagreement. Nearly 24% of CJD reported by the mortality register were false-positive diagnoses and 21.6% of the CJD cases diagnosed by the surveillance centre were not registered as CJD in the national mortality statistics. One out of 22 variant CJD cases was not reported as having any type of CJD in the mortality statistics. <i>Conclusions:</i>These findings raise doubt about the possibility of a reliable CJD surveillance only based on mortality data