Disease-Associated Mutant Ubiquitin Causes Proteasomal Impairment and Enhances the Toxicity of Protein Aggregates

Protein homeostasis is critical for cellular survival and its dysregulation has been implicated in Alzheimer's disease (AD) and other neurodegenerative disorders. Despite the growing appreciation of the pathogenic mechanisms involved in familial forms of AD, much less is known about the sporadic cases. Aggregates found in both familial and sporadic AD often include proteins other than those typically associated with the disease. One such protein is a mutant form of ubiquitin, UBB+1, a frameshift product generated by molecular misreading of a wild-type ubiquitin gene. UBB+1 has been associated with multiple disorders. UBB+1 cannot function as a ubiquitin molecule, and it is itself a substrate for degradation by the ubiquitin/proteasome system (UPS). Accumulation of UBB+1 impairs the proteasome system and enhances toxic protein aggregation, ultimately resulting in cell death. Here, we describe a novel model system to investigate how UBB+1 impairs UPS function and whether it plays a causal role in protein aggregation. We expressed a protein analogous to UBB+1 in yeast (Ubext) and demonstrated that it caused UPS impairment. Blocking ubiquitination of Ubext or weakening its interactions with other ubiquitin-processing proteins reduced the UPS impairment. Expression of Ubext altered the conjugation of wild-type ubiquitin to a UPS substrate. The expression of Ubext markedly enhanced cellular susceptibility to toxic protein aggregates but, surprisingly, did not induce or alter nontoxic protein aggregates in yeast. Taken together, these results suggest that Ubext interacts with more than one protein to elicit impairment of the UPS and affect protein aggregate toxicity. Furthermore, we suggest a model whereby chronic UPS impairment could inflict deleterious consequences on proper protein aggregate sequestration

Prions are a common mechanism for phenotypic inheritance in wild yeasts

The self-templating conformations of yeast prion proteins act as epigenetic elements of inheritance. Yeast prions might provide a mechanism for generating heritable phenotypic diversity that promotes survival in fluctuating environments and the evolution of new traits. However, this hypothesis is highly controversial. Prions that create new traits have not been found in wild strains, leading to the perception that they are rare “diseases” of laboratory cultivation. Here we biochemically test ~700 wild strains of Saccharomyces for [PSI(+)] or [MOT3(+)], and find these prions in many. They conferred diverse phenotypes that were frequently beneficial under selective conditions. Simple meiotic re-assortment of the variation harboured within a strain readily fixed one such trait, making it robust and prion-independent. Finally, we genetically screened for unknown prion elements. Fully one third of wild strains harboured them. These, too, created diverse, often beneficial phenotypes. Thus, prions broadly govern heritable traits in nature, in a manner that could profoundly expand adaptive opportunities

Paleoproterozoic (~1.88Ga) felsic volcanism of the Iricoumé Group in the Pitinga Mining District area, Amazonian Craton, Brazil: insights in ancient volcanic processes from field and petrologic data

The Iricoumé Group correspond to the most expressive Paleoproterozoic volcanism in the Guyana Shield, Amazonian craton. The volcanics are coeval with Mapuera granitoids, and belong to the Uatumã magmatism. They have U-Pb ages around 1880 Ma, and geochemical signatures of &#945;-type magmas. Iricoumé volcanics consist of porphyritic trachyte to rhyolite, associated to crystal-rich ignimbrites and co-ignimbritic fall tuffs and surges. The amount and morphology of phenocrysts can be useful to distinguish lava (flow and dome) from hypabyssal units. The morphology of ignimbrite crystals allows the distinction between effusive units and ignimbrite, when pyroclasts are obliterated. Co-ignimbritic tuffs are massive, and some show stratifications that suggest deposition by current traction flow. Zircon and apatite saturation temperatures vary from 799°C to 980°C, are in agreement with most temperatures of &#945;-type melts and can be interpreted as minimum liquidus temperature. The viscosities estimation for rhyolitic and trachytic compositions yield values close to experimentally determined melts, and show a typical exponential decay with water addition. The emplacement of Iricoumé volcanics and part of Mapuera granitoids was controlled by ring-faults in an intracratonic environment. A genesis related to the caldera complex setting can be assumed for the Iricoumé-Mapuera volcano-plutonic association in the Pitinga Mining District.<br>O Grupo Iricoumé corresponde ao mais expressivo vulcanismo Paleoproterozóico do Escudo das Guianas, craton Amazônico. As rochas vulcânicas são coexistentes com os granitóides Mapuera, e pertencem ao magmatismo Uatumã. Possuem idades U-Pb em torno 1888 Ma, e assinaturas geoquímicas de magmas tipo-A. As vulcânicas do Iricoumé consistem de traquitos a riolitos porfiríticos, associados a ignimbritos ricos em cristal e tufos co-ignimbríticos de queda e surge. A quantidade e a morfologia dos fenocristais podem ser utilizadas para distinguir lava (fluxo e domo) de unidades hipabissais. A morfologia dos cristais em ignimbritos permite a distinção entre unidades efusivas e ignimbritos, quando os piroclastos estão obliterados. Tufos co-ignimbríticos são maciços e alguns exibem estratificações que sugerem deposição por correntes de tração. Temperaturas de cristalização de zircão e apatita variam de 799°C a 980°C, são compatíveis com temperaturas de líquidos tipo-A e podem ser interpretadas como temperatura liquidus mínima. Estimativas de viscosidade para composições riolíticas e traquíticas fornecem valores próximos a de líquidos determinadas experimentalmente e ilustram curvas típicas de decaimento exponencial, com a adição de água. O posicionamento das vulcânicas Iricoumé e de parte dos granitóides Mapuera foi controlado por falhas anelares em ambiente intracratônico. Uma gênese relacionada a ambiente de complexo de caldeiras pode ser assumida para a associação vulcano-plutônica Iricoumé-Mapuera no Distrito Mineiro de Pitinga

Circulating cells as predictors of secondary manifestations of cardiovascular disease: design of the CIRCULATING CELLS study

Biomarkers for primary or secondary risk prediction of cardiovascular disease (CVD) are urgently needed to improve individual treatment and clinical trial design. The vast majority of biomarker discovery studies has concentrated on plasma/serum as an easily accessible source. Although numerous markers have been identified, their added predictive value on top of traditional risk factors has been limited, as the biological specimen does not specifically reflect expression profiles related with CVD progression and because the signal is often diluted by marker release from other organs. In contrast to serum markers, circulating cells serve as indicators of the actual disease state due to their active role in the pathogenesis of CVD and are responsible for the majority of secreted biomarkers. Therefore, the CIRCULATING CELLS study was initiated, focusing on the cellular effectors of atherosclerosis in the circulation. In total, 714 patients with coronary artery disease (CAD) symptoms were included. Blood cell fractions (monocytes, T-lymphocytes, platelets, granulocytes, PBMC) of all individual patients were isolated and stored for analysis. Concomitantly, extensive flow cytometric characterization of these populations was performed. From each patient, a detailed clinical profile together with extensive questionnaires about medical history and life style was obtained. Various high-throughput -omics approaches (protein, mRNA, miRNA) are currently being undertaken. Data will be integrated with advanced bioinformatics for discovery and validation of secondary risk markers for adverse events. Overall, the CIRCULATING CELLS study grants the interesting possibility that it will both identify novel biomarkers and provide useful insights into the pathophysiology of CAD in patient