Le malattie da prioni o encefalopatie spongiformi trasmissibili (TSE) sono malattie umane e animali conosciute da tempo e che hanno la particolare caratteristica di essere trasmissibili naturalmente o sperimentalmente. Sono anche definite dalla loro rarità, dal lungo periodo di incubazione, dalla loro evoluzione fatale senza remissione e senza alcuna reazione infiammatoria o immunitaria rilevabile, e da lesioni cerebrali che associano spongiosi, rarefazione neuronale, gliosi astrocitaria e depositi di proteine anormali che assumono talvolta l'aspetto di placche amiloidi. Le caratteristiche fisicochimiche e biologiche particolari dell'agente trasmissibile, unite al fatto che non è stato possibile evidenziare alcuna struttura indicativa di un microrganismo convenzionale e alcun acido nucleico specifico nei tessuti nonostante titoli infettivi elevati, hanno condotto Stanley B. Prusiner ad avanzare l'ipotesi di una proteina infettiva («prione» per proteinaceous infectious particle). Si ritiene che il prione sia la forma anormale di una proteina normale, la PrP, che nella sua forma cellulare, PrPc, è ancorata alla membrana cellulare di molti tessuti, in particolare dei neuroni, ed è sensibile alle proteasi. È acquisendo una conformazione spaziale anormale che la PrPc è convertita in proteina prionica scrapie (PrPsc), ricca di strati β plicati che le conferiscono le sue proprietà di parziale resistenza alle proteasi, di aggregazione e di insolubilità nei detergenti. Sebbene il legame tra l'accumulo di PrPsc e l'insorgenza delle lesioni sia discusso, la presenza di PrPsc è costante nel corso delle TSE e la sua evidenziazione è necessaria per la diagnosi di certezza. Le interazioni tra l'agente infettivo e il corredo genetico dell'ospite svolgono un ruolo determinante nello scatenamento e nello sviluppo di queste malattie. La scoperta del Kuru alla fine degli anni '50, la comparsa di casi iatrogeni negli anni '70, l'identificazione dell'encefalopatia spongiforme bovina nel 1985 e la rivelazione della sua trasmissione all'uomo 10 anni più tardi spiegano l'interesse per queste malattie ma anche i timori che hanno suscitato e continuano a suscitare per la salute pubblica. Esse restano peraltro un modello di ricerca appassionante, perché appartengono allo stesso tempo al gruppo delle malattie neurodegenerative da accumulo di proteine, al gruppo delle malattie trasmissibili ma anche al gruppo delle patologie genetiche, dal momento che alcune di esse sono a trasmissione mendeliana dominante. I concetti e le tecniche sviluppati nel campo dei prioni sono applicati in misura sempre maggiore ad altre malattie neurodegenerative, permettendo progressi teorici, metodologici e traslazionali.

1 Université Paris-Saclay, CEA, CNRS, Laboratoire des Maladies Neurodégénératives, 18 Route du Panorama, F-92265 Fontenay-aux-Roses, France. 2 Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Institut François Jacob, MIRCen, 18 Route du Panorama, F-92265 Fontenay-aux-Roses, France 3 ICM Institut du Cerveau et de la Moelle épinière, CNRS UMR7225, INSERM U1127, Sorbonne Université, Hôpital de la PitiéSalpêtrière, Paris, France 4 GIE Neuro-CEB/Neuropathologist Network: Plate-Forme de Ressources Biologiques, Bâtiment Roger Baillet, Hôpital de la Pitié-Salpêtrière, 47-83 boulevard de l'Hôpital, 75651 Paris Cedex 13. 5 Université de Lille, Inserm, CHU-Lille, Lille Neuroscience & Cognition, Alzheimer & Tauopathies, LabEx DISTALZ, Rue Polonovski, 59045 Lille, France 6 Laboratoire de Psychopathologie et de Neuropsychologie, EA, 2027, Université Paris 8, St-Denis, France

Protein misfolding cyclic amplification assay (PMCA) and real-time quaking-induced conversion (RT-QuIC) are two amplification techniques based on the ability of PrPsc to induce a conformational change in PrP allowing the detection of minute amounts of PrPsc in body fluids or tissues. PMCA and RT-QuIC have different ability to amplify PrPsc from sporadic, variant and genetic forms of Creutzfeldt-Jakob disease (CJD). PMCA readily amplifies PrPsc from variant CJD (vCJD) tissue while RT-QuIC easily amplifies PrPsc from sporadic CJD (sCJD) patient tissues. In terms of diagnosis, this implies the possibility of distinguishing vCJD from sCJD and explains the wider use of RT-QuIC given the respective frequencies of vCJD and sCJD. The sensitivity values of RT-QuIC for the diagnosis of sCJD are comparable or higher than those of the other tests (EEG, MRI, detection of 14-3-3 or tau proteins in cerebrospinal fluid) but with a specificity close to 100%. These new diagnostic methods could also be useful for the diagnosis of other neurodegenerative diseases.

Les tests effectués dans le liquide céphalorachidien sont particulièrement utiles pour différencier les maladies à prions d’autres démences dégénératives ou d’autres encéphalopathies dont certaines potentiellement traitables. La recherche ou les dosages des protéines 14-3-3, tau ou S100b, utilisés, depuis plusieurs années, sont des marqueurs indirects qui ont une bonne sensibilité mais une spécificité qui est loin d’atteindre 100 %. La possibilité maintenant de mettre en évidence directement la protéine prion anormale au moyen d’une méthode d’amplification, la Real-Time Quaking-Induced Conversion (RT-QuIC), permet, surtout pour la forme sporadique de la maladie de Creutzfeldt–Jakob, une importante amélioration du diagnostic de probabilité. Même si ceci a conduit en 2017 à la modification des critères diagnostiques de surveillance, la RT-QuIC doit encore être considérée comme une technique de recherche.

Prion diseases are fatal neurodegenerative disorders with sporadic, genetic or acquired etiologies. The molecular alterations leading to the onset and the spreading of these diseases are still unknown. In a previous work we identified a five-gene signature able to distinguish intracranially BSE-infected macaques from healthy ones, with SERPINA3 showing the most prominent dysregulation. We analyzed 128 suitable frontal cortex samples, from prion-affected patients (variant Creutzfeldt-Jakob disease (vCJD) n = 20, iatrogenic CJD (iCJD) n = 11, sporadic CJD (sCJD) n = 23, familial CJD (gCJD) n = 17, fatal familial insomnia (FFI) n = 9, Gerstmann–Sträussler–Scheinker syndrome (GSS)) n = 4), patients with Alzheimer disease (AD, n = 14) and age-matched controls (n = 30). Real Time-quantitative PCR was performed for SERPINA3 transcript, and ACTB, RPL19, GAPDH and B2M were used as reference genes. We report SERPINA3 to be strongly up-regulated in the brain of all human prion diseases, with only a mild up-regulation in AD. We show that this striking up-regulation, both at the mRNA and at the protein level, is present in all types of human prion diseases analyzed, although to a different extent for each specific disorder. Our data suggest that SERPINA3 may be involved in the pathogenesis and the progression of prion diseases, representing a valid tool for distinguishing different forms of these disorders in humans.

La transconformation (transmission de la conformation anormale) de protéines est un nouveau paradigme des maladies neurodégénératives, du vieillissement cérébral, de la myosite à inclusions sporadique, du diabète de type 2… Le repliement anormal se transmet d’une protéine à l’autre, puis d’une cellule à l’autre, comme le font les Prions. Dans le système nerveux, il survient dans quelques neurones et suit la direction du flux axonal ou la voie inverse. On distingue schématiquement trois types de propagation neuro-anatomique : « centripète » (synucléinopathie de la maladie de Parkinson où les lésions progressent des nerfs péricardiques, des plexus entériques… vers le méso et le néocortex ; la biopsie cutanée [« fenêtre ouverte sur le cerveau »] peut donc s’avérer un outil diagnostique), « centrifuge », du cortex vers le tronc cérébral (Aβ du vieillissement et la maladie d’Alzheimer, SOD et TDP-43 phosphorylée de la sclérose latérale amyotrophique) ou enfin « central » intéressant les réseaux neuronaux encéphaliques (TDP-43 de la variante comportementale de la démence frontotemporale). Les peptides Aβ et les protéines tau anormales de la maladie d’Alzheimer, longtemps considérés « centraux », sont aussi extracérébraux. L’exploration des mécanismes de la transconformation : intervention de protéines chaperones, formation de molécules labiles très toxiques (oligomères ?)… laisse entrevoir de multiples possibilités thérapeutiques.

The 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.

Protein misfolding and spreading ("transconformation") are being better understood. Described in Prions diseases, this new paradigm in the field of neurodegenerative disorders and brain aging also implies sporadic inclusion myositis, type 2 diabetes, some cancers, sickle cell disease... Misfolding is transmitted from a protein or peptide to a normally folded one. Often associated with a stress of the endoplasmic reticulum, it may spread along the neurites, following anterograde or retrograde axonal transport. In the central nervous system, it occurs in a few cells and there is invasion of adjacent cells by cell-to-cell spread. Three varieties of protein misfolding occur along neuroanatomical pathways. It can be a 'centripetal' process. The synucleinopathy of Parkinson disease has been carefully studied: the changes first occur in cardiac or enteric plexuses... and reach later on the mesencephalon and neocortex. Thus, skin biopsy might prove a diagnostic tool. Protein misfolding may also occur along 'centrifugal' pathways, from motor cortex to peripheral motor neurons. Examples are provided by SOD and pTDP-43 in Amyotrophic Lateral Sclerosis. Amyloid β peptide in cerebral aging and Alzheimer's disease also spread from occipital cortex to the brainstem. Lastly, the propagation may remain 'central' for TDP-43 in behavioral variant frontotemporal dementia, following only pathways of the encephalic neural network. This has to be confirmed, however, since the spreading of some proteins (such as tau or Aβ peptides) has been considered central for a long time and has proved today to involve extracerebral tissues. The complex mechanisms of protein misfolding, still in analysis, include the involvement of chaperone proteins, the formation of very toxic labile proteins molecules (oligomers?), and provide a number of new therapeutic perspectives.

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.

The subversion of the normal function exerted by the cellular prion protein (PrPC) in neurons by pathogenic prions is assumed to have a central role in the pathogenesis of transmissible spongiform encephalopathies. Using two murine models of prion infection, the 1C11 neuronal cell line and neurospheres, we document that prion infection is associated with the constitutive activation of signaling targets normally coupled with PrPC, including the Fyn kinase, the mitogen-associated protein kinases ERK1/2 and the CREB transcription factor. PrPC-dependent signaling overactivation in infected cells is associated with the recruitment of p38 and JNK stress-associated kinases. Downstream from CREB, prion-infected cells exhibit reduced activity of the matrix metalloprotease (MMP)-9. As MMP-9 catalyzes the degradation of the amyloid A-beta peptide, the decrease in MMP-9 activity in prion-infected cells causes a significant impairment of the clearance of A-beta, leading to its accumulation. By exploiting two 1C11-infected clones accumulating high or moderate levels of prions, we show that the prion-induced changes are correlated with the level of infectivity. Of note, a dose-dependent increase in A-beta levels was also found in the cerebrospinal fluid of mice inoculated with these infected clones. By demonstrating that pathogenic prions trigger increases in A-beta levels through the deviation of PrPC signaling, our data argue that A-beta may exacerbate prion-induced toxicity.

France, involved for a long time in the epidemiological surveillance of transmissible spongiform encephalopathy (TSE), created a national network of surveillance in 1991, because of the description of the first cases of Creutzfeldt-Jakob disease (CJD) linked to a treatment by growth hormone of human origin and the observation of cases of cats infected with the agent of the bovine spongiform encephalopathy in the United Kingdom (UK). The French surveillance network is integrated into the European network of surveillance since its creation in 1993. As in other countries, sporadic CJD is the most frequent form of TSE in France with an annual mortality rate of 1.44 per million. Genetic forms are most often associated with a mutation at codon 200. Among the cases of iatrogenic CJD, 13 cases of CJD after duramater grafts were observed and 119 related to treatment with growth hormone. France is the country worst affected in Europe and the world by this latter form, before the USA and UK. Since 1996, 27 cases of variant of CJD (vCJD) has been observed, making France the second country in the world most affected after the UK. No cases of transfusion-associated vCJD have been observed.

Les maladies à prions ou encéphalopathies spongiformes transmissibles sont des maladies rares dont il existe plusieurs formes (maladie de Creutzfeldt-Jakob [MCJ] sporadique, encéphalopathies subaiguës spongiformes génétiques, MCJ iatrogène, vMCJ). La forme sporadique est la plus fréquente et reste de cause inconnue. Le diagnostic clinique repose sur l’analyse des signes cliniques et le résultat de trois examens complémentaires : l’électroencéphalogramme, la recherche de la protéine 14-3-3 dans le liquide céphalorachidien (LCR) et l’imagerie par résonance magnétique. Le diagnostic de certitude est neuropathologique et biochimique (Western blot). En fonction du type biochimique et du polymorphisme du codon 129 du gène PRNP codant la protéine prion, on distingue plusieurs formes qui ont des présentations cliniques et des durées d’évolution variables. Les formes génétiques résultent de mutations ou d’insertions différentes dans le gène PRNP. La mutation E200K est la plus fréquente en France. La majorité des formes iatrogènes observées en France, sont secondaires à un traitement par hormone de croissance. Les greffes de dure-mère sont la seconde cause de formes iatrogènes. Un seul cas de contamination par du matériel chirurgical insuffisamment décontaminé a été rapporté. Aucun cas secondaire à des transfusions sanguines n’a été observé en France. Le nombre de cas iatrogènes est, dans notre pays comme dans le reste du monde, en nette diminution actuellement. La France est le second pays, après le Royaume-Uni, le plus touché par la forme variante liée à l’encéphalopathie spongiforme bovine (ESB). Il est maintenant démontré que les maladies sont identiques dans les deux pays et vraisemblablement secondaires à une contamination par la même souche de prion bovin. En pratique, toute suspicion de maladie à prions est à déclaration obligatoire (DO) auprès de l’Agence régionale de santé (ARS) à qui il faut aussi déclarer d’éventuels dons de sang ou actes invasifs datant de moins de six mois par rapport au début des signes cliniques. Un réseau de neuropathologie est en place depuis plusieurs années et permet, en facilitant la réalisation des autopsies, une meilleure surveillance et la détection de formes inhabituelles ou émergentes. Enfin dans l’avenir, les principaux défis qui restent à relever concernent l’amélioration de la spécificité des critères diagnostiques, la mise au point d’un test sanguin et le développement d’approches thérapeutiques efficaces.

Several molecular subtypes of sporadic Creutzfeldt-Jakob disease have been identified and electroencephalogram and cerebrospinal fluid biomarkers have been reported to support clinical diagnosis but with variable utility according to subtype. In recent years, a series of publications have demonstrated a potentially important role for magnetic resonance imaging in the pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease. Magnetic resonance imaging signal alterations correlate with distinct sporadic Creutzfeldt-Jakob disease molecular subtypes and thus might contribute to the earlier identification of the whole spectrum of sporadic Creutzfeldt-Jakob disease cases. This multi-centre international study aimed to provide a rationale for the amendment of the clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Patients with sporadic Creutzfeldt-Jakob disease and fluid attenuated inversion recovery or diffusion-weight imaging were recruited from 12 countries. Patients referred as 'suspected sporadic Creutzfeldt-Jakob disease' but with an alternative diagnosis after thorough follow up, were analysed as controls. All magnetic resonance imaging scans were assessed for signal changes according to a standard protocol encompassing seven cortical regions, basal ganglia, thalamus and cerebellum. Magnetic resonance imaging scans were evaluated in 436 sporadic Creutzfeldt-Jakob disease patients and 141 controls. The pattern of high signal intensity with the best sensitivity and specificity in the differential diagnosis of sporadic Creutzfeldt-Jakob disease was identified. The optimum diagnostic accuracy in the differential diagnosis of rapid progressive dementia was obtained when either at least two cortical regions (temporal, parietal or occipital) or both caudate nucleus and putamen displayed a high signal in fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging. Based on our analyses, magnetic resonance imaging was positive in 83% of cases. In all definite cases, the amended criteria would cover the vast majority of suspected cases, being positive in 98%. Cerebral cortical signal increase and high signal in caudate nucleus and putamen on fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging are useful in the diagnosis of sporadic Creutzfeldt-Jakob disease. We propose an amendment to the clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease to include findings from magnetic resonance imaging scans.

B. A. Faucheux, E. Morain, V. Diouron, J.‐P. Brandel, D. Salomon, V. Sazdovitch, N. Privat, J.‐L. Laplanche, J.‐J. Hauw and S. Haïk (2011) Neuropathology and Applied Neurobiology37, 500–512 Quantification of surviving cerebellar granule neurones and abnormal prion protein (PrPSc) deposition in sporadic Creutzfeldt–Jakob disease supports a pathogenic role for small PrPSc deposits common to the various molecular subtypes Aims: Neuronal death is a major neuropathological hallmark in prion diseases. The association between the accumulation of the disease‐related prion protein (PrPSc) and neuronal loss varies within the wide spectrum of prion diseases and their experimental models. In this study, we investigated the relationships between neuronal loss and PrPSc deposition in the cerebellum from cases of the six subtypes of sporadic Creutzfeldt–Jakob disease (sCJD; n = 100) that can be determined according to the M129V polymorphism of the human prion protein gene (PRNP) and PrPSc molecular types. Methods: The numerical density of neurones was estimated with a computer‐assisted image analysis system and the accumulation of PrPSc deposits was scored. Results: The scores of PrPSc immunoreactive deposits of the punctate type (synaptic type) were correlated with neurone counts – the higher the score the higher the neuronal loss – in all sCJD subtypes. Large 5‐ to 50‐µm‐wide deposits (focal type) were found in sCJD‐MV2 and sCJD‐VV2 subtypes, and occasionally in a few cases of the other studied groups. By contrast, the highest scores for 5‐ to 50‐µm‐wide deposits observed in sCJD‐MV2 subtype were not associated with higher neuronal loss. In addition, these scores were inversely correlated with neuronal counts in the sCJD‐VV2 subtype. Conclusions: These results support a putative pathogenic role for small PrPSc deposits common to the various sCJD subtypes. Furthermore, the observation of a lower loss of neurones associated with PrPSc type‐2 large deposits is consistent with a possible ‘protective’ role of aggregated deposits in both sCJD‐MV2 and sCJD‐VV2 subtypes.

Las enfermedades por priones o encefalopatías espongiformes transmisibles son enfermedades de humanos y animales que se conocen desde hace mucho tiempo y que tienen la particularidad de transmitirse de forma natural o experimental. También se definen por su escasa frecuencia, su largo período de incubación, su evolución fatal sin remisión, sin reacción inflamatoria o inmunitaria detectable, y por las lesiones cerebrales, que asocian espongiosis, rarefacción neuronal y gliosis astrocítica. En los seres humanos se distinguen formas esporádicas, genéticas e infecciosas. Su diagnóstico es a veces difícil. Además del electroencefalograma y el estudio de líquido cefalorraquídeo (LCR) con detección de la proteína 14-3-3, la resonancia magnética (RM) cerebral a menudo permite proporcionar elementos a favor del diagnóstico, cuya certeza, sin embargo, sólo se obtiene con la exploración neuropatológica del cerebro. Desde el punto de vista práctico, su diagnóstico permite la aplicación de medidas preventivas dirigidas a prevenir la transmisión secundaria, la inclusión en protocolos terapéuticos y el ofrecimiento de consejo genético en las formas familiares.

Cerebrovascular disease (CVD) is a severe complication associated with sickle cell anemia. Abnormal transcranial Doppler (TCD) identifies some children at high risk, but other markers would be helpful. This cohort study was aimed at evaluating the effects of genetic biomarkers on the risk of developing CVD in children from Minas Gerais, Brazil. Clinical and hematological data were retrieved from children's records. Outcomes studied were overt ischemic stroke and CVD (overt ischemic stroke, transient ischemic attack, abnormal TCD, or abnormal cerebral angiography). Out of 411 children, 386 (93.9%) had SS genotype, 23 (5.6%) had Sβ0-thal and two had severe Sβ+-thal (0.5%). Frequency of CVD was lower in Sβ-thal group (p = 0.05). No effect of VCAM-1 polymorphism on stroke or CVD risks was detected. Cumulative incidence of stroke was significantly higher for children with TNF-α A allele (p = 0.02) and lower for children with HBA deletion (p = 0.02). However, no association between CVD and TNF-α -308G>A was found. CVD cumulative incidence was significantly lower for children with HBA deletion (p = 0.004). This study found no association between VCAM1 c.1238G>C and stroke. An association between stroke and TNF-α -308A allele has been suggested. Our results have confirmed the protective role of HBA deletion against stroke and CVD.