Involvement of Dab1 in APP processing and [beta]-amyloid deposition in sporadic Creutzfeldt-Jakob patients.

Alzheimer"s disease and prion pathologies (e.g., Creutzfeldt-Jakob disease) display profound neural lesions associated with aberrant protein processing and extracellular amyloid deposits. For APP processing, emerging data suggest that the adaptor protein Dab1 plays a relevant role in regulating its intracellular trafficking and secretase-mediated proteolysis. Although some data have been presented, a putative relationship between human prion diseases and Dab1/APP interactions is lacking. Therefore, we have studied the putative relation between Dab1, APP processing and Aβ deposition, targets in sCJD cases. Our biochemical results categorized two groups of sCJD cases, which also correlated with PrPsc types 1 and 2 respectively. One group, with PrPsc type 1 showed increased Dab1 phosphorylation, and lower βCTF production with an absence of Aβ deposition. The second sCJD group, which carried PrPsc type 2, showed lower levels of Dab1 phosphorylation and βCTF production, similar to control cases. Relevant Aβ deposition in the second sCJD group was measured. Thus, a direct correlation between Dab1 phosphorylation, Aβ deposition and PrPsc type in human sCJD is presented for the first time.

Neuroprotective role of PrPC against kainate-induced epileptic seizures and cell death depends on the modulation of JNK3 activation by GluR6/7-PSD-95 binding

Cellular prion protein (PrPC) is a glycosyl-phosphatidylinositol¿anchored glycoprotein. When mutated or misfolded, the pathogenic form (PrPSC) induces transmissible spongiform encephalopathies. In contrast, PrPC has a number of physiological functions in several neural processes. Several lines of evidence implicate PrPC in synaptic transmission and neuroprotection since its absence results in an increase in neuronal excitability and enhanced excitotoxicity in vitro and in vivo. Furthermore, PrPC has been implicated in the inhibition of N-methyl-D-aspartic acid (NMDA)¿mediated neurotransmission, and prion protein gene (Prnp) knockout mice show enhanced neuronal death in response to NMDA and kainate (KA). In this study, we demonstrate that neurotoxicity induced by KA in Prnp knockout mice depends on the c-Jun N-terminal kinase 3 (JNK3) pathway since Prnpo/oJnk3o/o mice were not affected by KA. Pharmacological blockage of JNK3 activity impaired PrPC-dependent neurotoxicity. Furthermore, our results indicate that JNK3 activation depends on the interaction of PrPC with postsynaptic density 95 protein (PSD-95) and glutamate receptor 6/7 (GluR6/7). Indeed, GluR6¿PSD-95 interaction after KA injections was favored by the absence of PrPC. Finally, neurotoxicity in Prnp knockout mice was reversed by an AMPA/KA inhibitor (6,7-dinitroquinoxaline-2,3-dione) and the GluR6 antagonist NS-102. We conclude that the protection afforded by PrPC against KA is due to its ability to modulate GluR6/7-mediated neurotransmission and hence JNK3 activation.

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Reggies/flotillins regulate E-cadherin-mediated cell contact formation by affecting EGFR trafficking.

The reggie/flotillin proteins are implicated in membrane trafficking and, together with the cellular prion protein (PrP), in the recruitment of E-cadherin to cell contact sites. Here, we demonstrate that reggies, as well as PrP down-regulation, in epithelial A431 cells cause overlapping processes and abnormal formation of adherens junctions (AJs). This defect in cell adhesion results from reggie effects on Src tyrosine kinases and epidermal growth factor receptor (EGFR): loss of reggies reduces Src activation and EGFR phosphorylation at residues targeted by Src and c-cbl and leads to increased surface exposure of EGFR by blocking its internalization. The prolonged EGFR signaling at the plasma membrane enhances cell motility and macropinocytosis, by which junction-associated E-cadherin is internalized and recycled back to AJs. Accordingly, blockage of EGFR signaling or macropinocytosis in reggie-deficient cells restores normal AJ formation. Thus, by promoting EGFR internalization, reggies restrict the EGFR signaling involved in E-cadherin macropinocytosis and recycling and regulate AJ formation and dynamics and thereby cell adhesion.

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Protein destabilization by mutations or external stresses may lead to misfolding and aggregation in the cell. Often, damage is not limited to a simple loss of function, but the hydrophobic exposure of aggregate surfaces may impair membrane functions and promote the aggregation of other proteins. Such a "proteinacious infectious" behavior is not limited to prion diseases. It is associated to most protein-misfolding neurodegenerative diseases and to aging in general. With the molecular chaperones and proteases, cells have evolved powerful tools that can specifically recognize and act upon misfolded and aggregated proteins. Whereas some chaperones passively prevent aggregate formation and propagation, others actively unfold and solubilize stable aggregates. In particular, ATPase chaperones and proteases serve as an intracellular defense network that can specifically identify and actively remove by refolding or degradation potentially infectious cytotoxic aggregates. Here we discuss two types of molecular mechanisms by which ATPase chaperones may actively solubilize stable aggregates: (1) unfolding by power strokes, using the Hsp100 ring chaperones, and (2) unfolding by random movements of individual Hsp70 molecules. In bacteria, fungi, and plants, the two mechanisms are key for reducing protein damages from abiotic stresses. In animals devoid of Hsp100, Hsp70 appears as the core element of the chaperone network, preventing the formation and actively removing disease-causing protein aggregates.

Familial frontotemporal dementia with ubiquitin inclusion bodies and without motor neuron disease.

Frontotemporal dementia (FTD) is the second most common degenerative dementia after Alzheimer's disease and its Lewy body variant. Clinical pathology can be subdivided in three main neuropathological subtypes: frontal lobe dementia, Pick's disease and FTD with motor neuron disease (MND), all characterised by distinct histological features. Until recently the presence of ubiquitin-positive intraneuronal inclusions in the dentate gyrus, and the temporal and frontal cortex was usually associated with the MND type. Such inclusions were also observed in a few sporadic cases of FTD without or with parkinsonism (FTDP) in the absence of MND. We present here clinical, neuropathological and immunohistochemical data about a Swiss FTD family with FTDP-like features but without MND. Spongiosis and mild gliosis were observed in the grey matter. No neurofibrillary tangles, Pick bodies, Lewy bodies, senile plaques or prion-positive signals were present. However, ubiquitin-positive intracytoplasmic inclusions were detected in various structures but predominantly in the dentate gyrus. These observations support the existence of a familial form of FTDP with ubiquitin-positive intracytoplasmic inclusions (Swiss FTDP family).

Detection of PrPres in genetically susceptible fetuses from sheep with natural scrapie

Scrapie is a transmissible spongiform encephalopathy with a wide PrPres dissemination in many non-neural tissues and with high levels of transmissibility within susceptible populations. Mechanisms of transmission are incompletely understood. It is generally assumed that it is horizontally transmitted by direct contact between animals or indirectly through the environment, where scrapie can remain infectious for years. In contrast, in utero vertical transmission has never been demonstrated and has rarely been studied. Recently, the use of the protein misfolding cyclic amplification technique (PMCA) has allowed prion detection in various tissues and excretions in which PrPres levels have been undetectable by traditional assays. The main goal of this study was to detect PrPres in fetal tissues and the amniotic fluid from natural scrapie infected ewes using the PMCA technique. Six fetuses from three infected pregnant ewes in an advanced clinical stage of the disease were included in the study. From each fetus, amniotic fluid, brain, spleen, ileo-cecal valve and retropharyngeal lymph node samples were collected and analyzed using Western blotting and PMCA. Although all samples were negative using Western blotting, PrPres was detected after in vitro amplification. Our results represent the first time the biochemical detection of prions in fetal tissues, suggesting that the in utero transmission of scrapie in natural infected sheep might be possible.

APP processing and b-amyloid deposition in sporadic Creutzfeldt-Jakob patients is dependent on Dab1.

Alzheimer"s disease and prion pathologies (e.g., Creutzfeldt-Jakob disease (CJD)) display profound neural lesions associated with aberrant protein processing and extracellular amyloid deposits. Dab1 has been implicated in the regulation of Amyloid Precursor Protein (APP), but a direct link between human prion diseases and Dab1/APP interactions has not been published. Here we examined this putative relationship in seventeen cases of sporadic CJD (sCJD) post mortem. Biochemical analyses of brain tissue revealed two groups, which also correlated with PrPsc types 1 and 2. One group, with PrPsc type 1 showed increased Dab1 phosphorylation, and lower CTF production with an absence of A deposition. The second sCJD group, which carried PrPsc type 2, showed lower levels of Dab1 phosphorylation and CTF production, and A deposition. Thus, the present observations suggest a correlation between Dab1-phosphorylation, A deposition and PrPsc type in sCJD.

A common BACE1 polymorphism is a risk factor for sporadic Creutzfeldt-Jakob disease

The β site APP cleaving enzyme 1 (BACE1) is the rate-limiting β-secretase enzyme in the amyloidogenic processing of APP and Aβ formation, and therefore it has a prominent role in Alzheimer"s disease (AD) pathology. Recent evidence suggests that the prion protein (PrP) interacts directly with BACE1 regulating its β-secretase activity. Moreover, PrP has been proposed as the cellular receptor involved in the impairment of synaptic plasticity and toxicity caused by Aβ oligomers. Provided that common pathophysiologic mechanisms are shared by Alzheimer"s and Creutzfeldt-Jakob (CJD) diseases, we investigated for the first time to the best of our knowledge a possible association of a common synonymous BACE1 polymorphism (rs638405) with sporadic CJD (sCJD). Our results indicate that BACE1 C-allele is associated with an increased risk for developing sCJD, mainly in PRNP M129M homozygous subjects with early onset. These results extend the very short list of genes (other than PRNP) involved in the development of human prion diseases; and support the notion that similar to AD, in sCJD several loci may contribute with modest overall effects to disease risk. These findings underscore the interplay in both pathologies of APP, Aβ oligomers, ApoE, PrP and BACE1, and suggest that aging and perhaps vascular risk factors may modulate disease pathologies in part through these key players

Neurodegenerative diseases: A protein misfolding consequence

Protein misfolding and aggregation into amyloid-like structures is related with an increasing number of both non-neuropathic (either localized or systemic) and neurodegenerative human disorders. Decrypting the mechanisms and implications underlying amyloid assemblies has become a central issue in biology and medicine. Compelling evidence show that the formation of amyloid aggregates has a negative impact in cell physiology, entailing the cell dysfunction and finally apoptosis and cell death. The aim of the present review is to illustrate the currently status of the most common and/or debilitating conformational diseases, from Alzheimer to prion diseases.

Neurodegenerative diseases: A protein misfolding consequence

Protein misfolding and aggregation into amyloid-like structures is related with an increasing number of both non-neuropathic (either localized or systemic) and neurodegenerative human disorders. Decrypting the mechanisms and implications underlying amyloid assemblies has become a central issue in biology and medicine. Compelling evidence show that the formation of amyloid aggregates has a negative impact in cell physiology, entailing the cell dysfunction and finally apoptosis and cell death. The aim of the present review is to illustrate the currently status of the most common and/or debilitating conformational diseases, from Alzheimer to prion diseases.

The powerful high pressure tool for protein conformational studies

The pressure behavior of proteins may be summarized as a the pressure-induced disordering of their structures. This thermodynamic parameter has effects on proteins that are similar but not identical to those induced by temperature, the other thermodynamic parameter. Of particular importance are the intermolecular interactions that follow partial protein unfolding and that give rise to the formation of fibrils. Because some proteins do not form fibrils under pressure, these observations can be related to the shape of the stability diagram. Weak interactions which are differently affected by hydrostatic pressure or temperature play a determinant role in protein stability. Pressure acts on the 2º, 3º and 4º structures of proteins which are maintained by electrostatic and hydrophobic interactions and by hydrogen bonds. We present some typical examples of how pressure affects the tertiary structure of proteins (the case of prion proteins), induces unfolding (ataxin), is a convenient tool to study enzyme dissociation (enolase), and provides arguments to understand the role of the partial volume of an enzyme (butyrylcholinesterase). This approach may have important implications for the understanding of the basic mechanism of protein diseases and for the development of preventive and therapeutic measures.

Some physico-chemical parameters that influence proteinase K resistance and the infectivity of PrP Sc after high pressure treatment

Crude brain homogenates of terminally diseased hamsters infected with the 263 K strain of scrapie (PrP Sc) were heated and/or pressurized at 800 MPa at 60ºC for different times (a few seconds or 5, 30, 120 min) in phosphate-buffered saline (PBS) of different pH and concentration. Prion proteins were analyzed on immunoblots for their proteinase K (PK) resistance, and in hamster bioassays for their infectivity. Samples pressurized under initially neutral conditions and containing native PrP Sc were negative on immunoblots after PK treatment, and a 6-7 log reduction of infectious units per gram was found when the samples were pressurized in PBS of pH 7.4 for 2 h. A pressure-induced change in the protein conformation of native PrP Sc may lead to less PK resistant and less infectious prions. However, opposite results were obtained after pressurizing native infectious prions at slightly acidic pH and in PBS of higher concentration. In this case an extensive fraction of native PrP Sc remained PK resistant after pressure treatment, indicating a protective effect possibly due to induced aggregation of prion proteins in such buffers.

Prions: the danger of biochemical weapons

The knowledge of biotechnology increases the risk of using biochemical weapons for mass destruction. Prions are unprecedented infectious pathogens that cause a group of fatal neurodegenerative diseases by a novel mechanism. They are transmissible particles that are devoid of nucleic acid. Due to their singular characteristics, Prions emerge as potential danger since they can be used in the development of such weapons. Prions cause fatal infectious diseases, and to date there is no therapeutic or prophylactic approach against these diseases. Furthermore, Prions are resistant to food-preparation treatments such as high heat and can find their way from the digestive system into the nervous system; recombinant Prions are infectious either bound to soil particles or in aerosols. Therefore, lethal Prions can be developed by malicious researchers who could use it to attack political enemies since such weapons cause diseases that could be above suspicion.

Français 847

Contient : 1° Chansons ; « LI CHASTELAINS DE COUCI » ; « BLONDIAUS DE NEELE » ; « LI ROIS DE NAVARE » ; « Mesire GAUTIERS D'ARGIES » ; « MONIOT D'ARRAZ » ; « MONIOT DE PARIS » ; « MONIOT D'ARRAZ » ; « MONIOT DE PARIS » ; « TIEBAUT DE BLAZON » ; « Mestre RICHART DE FURNIVAL » ; « Mesire GAUTIER D'ARGIES » ; « JAQUES D'OSTUN » ; « Le filz mestre BAUDOIN L'ORGUENEUR » ; « LI VISDAME DE CHARTRES » ; « ROBERT DE BLOIS » ; « ROBERT DE RAINS » ; « RAOUL DE FERRIERES » ; « GONTIERS DE SOIGNIES » ; « VIELARS DE CORBIE » ; « BURNIAUS DE TORS » ; « BAUDE DE LA QUARRIERE » ; « AUBIN DE SEZANE » ; « Mesire ROBERT DE MARBEROLES » ; « JEHAN ERARS » ; « PERRIN D'ANGECORT » ; « Mesire RAOUL DE SOISONS » ; « Mesire HUGUE DE BRESIL » ; « LI DUX DE BREBEN » ; « COLARS LI BOTEILLIERS » ; « ROGERT DE CANBRAI » ; « GOBIN DE RAINS » ; « JEHAN ERARS » ; « Mestre RICHART DE SEMILLI » ; « MONIOT DE PARIS » ; « Mestre RICHART DE SEMILLI » ; « MONIOT DE PARIS » ; « GILLE DE MESON » ; « Mestre GILLES LI VINIERS » ; « Mestre SIMON D'AUTIE » ; « ODART DE LACENI » ; « CHANOINES DE ST-QUENTIN » ; « BAUDOIN DES AUTIEUS » ; « Mesire PIERRE DE CREON » ; « LI CHASTELAINS D'ARRAZ » ; « LI TRESORIERS DE LILLE » ; « BAUDOIN DES AUTIEUS » ; « CHARDONS » [de Reims] ; « LA CHIEVRE DE RAINS » ; « SAUVAGE D'ARRAZ » ; « JEHANOT PAON DE PARIS » ; « GILLEBERT DE BERNEVILE » ; « GAUTIER D'ESPINAIS » ; « COLIN MUSET » ; « JAQUES DE HEDINC » ; « PERRIN D'ANGECORT » ; « Mesire JAQUES DE CHISON » ; « RAOUL DE BEAUVES » ; « LI CUENS D'ANJOU » ; « HUITACES DE FONTAINES » ; Chansons dont les noms des auteurs manquent ; « Desconfortez et de joie partiz ». [GAUTIER D'ESPINAUS] ; « Quant voi le douz tens bel et cler » ; « Quant voi le douz tens revenir » ; « Chançon vueil fere de moi ». [PERRIN D'ANGECOURT] ; « Trop est mes maris jalos ». (PERRIN D'ANGECOURT.) ; « Avant hier en un vert pré » ; « Trop par est cist mondes cruaus » ; « Qui à chanter veut entendre » ; « Au conmencier de ma nouvele. amor ». [GAUTIERS D'ESPINAUS, QUESNES DE BETHUNE, ou CHEVALIER] ; « Quant florist la prée ». (GAUTIERS D'ESPINAUS, QUESNES DE BETHUNE, ou CHEVALIER.) ; « Souvent souspire » ; « Par mainte foiz m'ont mesdisanz grevé » ; « Flor ne verdor ne m'a pleü » ; « J'ai fait maint vers de chançon ». [GILLEBERT DE BERNEVILLE] ; La même qu'au Fol. 116 ; « Por le tens qui verdoie ». [GOBIN DE REIMS] ; La même qu'au Fol. 94 ; « Tel nuist qui ne puet aidier » ; « Apris ai qu'en chantant plor » ; « Cil qui chantent de flor ne de verdure ». [EUSTACHE DE REIMS.] ; « Bele dame me prie de chanter ». [LE CHATELAIN DE COUCI] ; « Qui d'amors a remenbrance ». [ROBERT DE MEMBEROLLES, ou GILLES DE VIESMAISONS] ; « Chanter voil un novel son » ; « Amors qui souprent » ; « Quant li dous tens renouvele » ; « En pascor un jor erroie » ; « Au partir d'esté et de flors » ; « Amors est trop fiers chastelains » ; « Chanter me covient pla[ins] d'ire » ; « De mon desir ne sai mon melz eslire ». [BLONDEL] ; « Au tens d'esté que voi vergier florir ». [ROBERT MAUVOISIN] ; « A l'entrant du douz termine ». [GACE BRULE, ou MORISSE DE CRAON.] ; « A la douçor du tens qui raverdoie » ; « Au reperier que je fis de Prouvence » ; « Bien voi que ne puis morir ». [THIBAUT DE BLAZON.] ; « Contre tens que voi frimer ». [GACE BRULE, ou GAUTIER D'ARGIES] ; La même qu'au Fol. 65 ; « Ce fu l'autrier en.I. autre païs ». [QUESNES DE BETHUNE, ou RICHART DE FOURNIVAL] ; « Chanter et renvoisier suel ». [THIBAUT DE BLAZON.] ; « Conmencement de douce seson bele ». [GAUTIER D'ESPINAUS] ; « Amors qui m'a tolu à moi ». [CHRESTIEN DE TROYES] ; « Dame ensi est qu'il me couvient ». [LE ROI DE NAVARRE.] ; « Contre la froidor ». [JACQUES DE CISOING, ou PERRIN D'ANGECOURT] ; « James ne cuidai avoir ». [PERRIN D'ANGECOURT] ; « Il feroit trop bon morir ». [PERRIN D'ANGECOURT.] ; « Amors me plaig plus que de tot » ; « Por moi renvoisier » ; « Ja de chanter en ma vie ». [GAGE BRULE] ; « Car me conseilliez, Jehan, se Dex vos voie » ; « Quant voi la prime florete » ; « Huimain par.I. ajornant » ; « Quant voi la fleur nouvele » ; « Las ! por qoi m'entremis d'amer » ; « Merveilles est que toz jors woil chanter ». « GUILLAUME » [LE VINIER ?] ; « Li chastelains de Couci ama tant » ; « Amors me tient en esperance » ; « Jolif, plain de bone amor » ; « Bien ait l'amor dont l'on cuide avoir joie ». [GACE BRULE.] ; « A ma dame ai pris congié ». [MONIOT D'ARRAS] ; « Quant li boscage retentist ». [JEHAN DE NEUVILLE.] ; « En mai la rosée que nest la flor » ; « James chançon ne ferai » ; « Heneur et bone aventure ». [PERRIN D'ANGECOURT] ; « Quant iver trait à fin » ; « Un petit devant le jor » ; « E! serventois, arriere t'en revas ». [ALART DE CAUS] ; « Por verdure ne por prée ». [GACE BRULE.] ; « Rose ne lis ne ne donnent talent ». [CARDON DES CROISILLES] ; « Mar vit reson qui couvoite trop haut ». [CARDON DES CROISILLES] ; « Je chevauchoie l'autrier ». [MONIOT DE PARIS.] ; « L'autrier tot seul chevauchoie mon chemin ». [RICHART DE SEMILLI] ; « Quant voi blanchoier la fleur » ; « Por le tens qui verdoie ». [GOBIN DE REIMS] ; La même qu'au Fol. 94 et 139 ; « Trop ai longuement » ; « Tot soit mes cuers en grant desesperance ». [EUDES DE LA COURROIERIE.] ; « Je chant par droite reson » ; « Se j'ai du monde la flor » ; « L'autrier m'en aloie » ; « Lasse ! por quoi refusai » ; « Quant-la rosée el mois de mai » ; « Je ne mi woil de bone amor retraire » ; « Trop sui d'amors enganez » ; « Des or mes ne me puis tere » ; « Quant je voi esté venir » ; « De jolif cuer enamoré ». [LE COMTE DE ROUCI, ou MONIOT D'ARRAS.] ; « Le cuer se vait de l'oil pleignant » ; « Quant l'aube espine fleurist ». [JACQUES DE CISOING] ; « Quant mars conmence et fevrier faut » ; « De chanter m'est pris corage ». [RICHART DE SEMILLI] ; « Quant je oi chanter l'aloete ». [MONIOT DE PARIS] ; « Li rosignol que j'oi chanter ». [PIERRE LE BORGNE de Lille] ; « L'autrier chevanchoie delez Paris ». [RICHART DE SEMILLI.] ; « En une praele » ; « Joliveté et bone amor m'ensaigne ». [JEHAN D'ESQUIRI] ; « Au renouvel, du tens que la florete » ; « Par le tens bel » ; « Force d'amor me fet dire » ; « Por mon cuer à joie atrere » ; « Chanterai par grant envie » ; « Au tens pascor ». [JEHAN ERART] ; « Contre le tens que je voi qui repere » ; « M'amors je fui norris » ; « Qui bien aime à tart oublie » ; « Mere au roi puissant » ; « Lonc tens ai usé » ; « Prion en chantant » ; « On doit la mere Dieu honorer » ; « Chanter vos woil de la virge Marie » ; « De la tres douce Marie voil chanter » ; « Mout sera cil bien norris » ; « Fox est qui en folie ». « Li QUENS DE BRETAIGNE » ; « Bernart à vous weil demander » ; « Chanter me fet ma dame que j'aim tant » ; « Nouviaument m'est pris envie » ; « Longuement ai esté pensis » ; « Haute chanson de haute estoire di » ; Chanson anonyme : ; « Je feré chançon novelle » ; 2° « Li Romans du vergier et de l'arbre d'amours » ; 3° « ADANS DE LE HALE »