Identification of human proteins that modify misfolding and proteotoxicity of pathogenic ataxin-1

Proteins with long, pathogenic polyglutamine (polyQ) sequences have an enhanced propensity to spontaneously misfold and self-assemble into insoluble protein aggregates. Here, we have identified 21 human proteins that influence polyQ-induced ataxin-1 misfolding and proteotoxicity in cell model systems. By analyzing the protein sequences of these modifiers, we discovered a recurrent presence of coiled-coil (CC) domains in ataxin-1 toxicity enhancers, while such domains were not present in suppressors. This suggests that CC domains contribute to the aggregation- and toxicity-promoting effects of modifiers in mammalian cells. We found that the ataxin-1–interacting protein MED15, computationally predicted to possess an N-terminal CC domain, enhances spontaneous ataxin-1 aggregation in cell-based assays, while no such effect was observed with the truncated protein MED15ΔCC, lacking such a domain. Studies with recombinant proteins confirmed these results and demonstrated that the N-terminal CC domain of MED15 (MED15CC) per se is sufficient to promote spontaneous ataxin-1 aggregation in vitro. Moreover, we observed that a hybrid Pum1 protein harboring the MED15CC domain promotes ataxin-1 aggregation in cell model systems. In strong contrast, wild-type Pum1 lacking a CC domain did not stimulate ataxin-1 polymerization. These results suggest that proteins with CC domains are potent enhancers of polyQ-mediated protein misfolding and aggregation in vitro and in vivo

Bedeutung von Isolation, Flaechengroesse und Biotopqualitaet fuer das Ueberleben von Tier- und Pflanzenpopulationen in der Kulturlandschaft am Beispiel von Trockenstandorten. Teilprojekt 5: Demographische Analyse mobiler Leitarten Endbericht

We worked out the methodology for a population viability analysis for target species with different mobility. Conservation strategies based on key factors of habitat quality and population dynamics were developed. The following species were investigated: the grasshopper Platycleis albopunctata, the butterfly Melitaea didyma and the birds Lullula arborea and Lanius excubitor. In the field data on habitat structure, on breeding and batching success as well as on dispersal were gained. The key factors for the single species are: micro climate at the oviposition site for Platycleis albopunctata, growth form and position of oviposition plant for Melitaea didyma, perches and usable area for Lanius excubitor and bare ground for Lullula arborea. The following strategies of habitat selection in conjunction with the population dynamics were observed: 1. Platyleis albopunctata is limited by the climate. In optimal habitats the temperature sum is sufficient for in time developement even in years with unfavourable weather conditions. 2. Habitat quality in Melitaea didyma determined by the availability of oviposition plants in sparse vegetation and by nectare supply. Both factors can be guaranteed by the right grazing regime. Because of the high mobility of the species also patches in which Melitaea eventually went extinct because of too intensive grazing can be recolonized. 3. Lanius excubitor occupies different quality habitats. A few optimal habitats function as a source and the survival of the population is mainly dependent on these habitats. The importance of suboptimal habitats depends on the conditions in the population. Marginal habitats do not seem to have a numerical effect on the survival. 4. Landscape dynamics drives the population dynamics of Lullula arborea. Newly emerging habitats are easily colonized, but at the same time they are lost quickly in the course of succession. (orig.)SIGLEAvailable from TIB Hannover: F97B2399a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman

Core structure of extensive air showers at primary energies around the knee by a multifractal moments analysis

A system of large-area position-sensitive multiwire proportional chambers (MWPC), installed below the hadron calorimeter of the central detector of the KASCADE (Karlsruhe shower core and array detector) experiment is able to observe the density distributions of high-energy muons and of the high-energy tails of the hadron spectrum in the core of extensive air showers (EAS). Applying a classification by multifractal moments of the observed patterns allows to explore the information on mass composition of cosmic rays in the studied energy region. Additionally correlating with the shower size and the number of reconstructed muons in the core region, an artificial neural net analysis leads to probability distributions for associating single showers to particular primary masses. The classification can serve as basis of a more detailed shower specification considering further measured shower parameters. (orig.)26 refs.Available from TIB Hannover: ZA 5141(6105) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

The Role of the Sodium-Taurocholate Cotransporting Polypeptide (NTCP) and of the Bile Salt Export Pump (BSEP) in Physiology and Pathophysiology of Bile Formation

Bile formation is an important function of the liver. Bile salts are a major constituent of bile and are secreted by hepatocytes into bile and delivered into the small intestine, where they assist in fat digestion. In the small intestine, bile salts are almost quantitatively reclaimed and transported back via the portal circulation to the liver. In the liver, hepatocytes take up bile salts and secrete them again into bile for ongoing enterohepatic circulation. Uptake of bile salts into hepatocytes occurs largely in a sodium-dependent manner by the sodium taurocholate cotransporting polypeptide NTCP. The transport properties of NTCP have been extensively characterized. It is an electrogenic member of the solute carrier family of transporters (SLC10A1) and transports predominantly bile salts and sulfated compounds, but is also able to mediate transport of additional substrates, such as thyroid hormones, drugs and toxins. It is highly regulated under physiologic and pathophysiologic conditions. Regulation of NTCP copes with changes of bile salt load to hepatocytes and prevents entry of cytotoxic bile salts during liver disease. Canalicular export of bile salts is mediated by the ATP-binding cassette transporter bile salt export pump BSEP (ABCB11). BSEP constitutes the rate limiting step of hepatocellular bile salt transport and drives enterohepatic circulation of bile salts. It is extensively regulated to keep intracellular bile salt levels low under normal and pathophysiologic situations. Mutations in the BSEP gene lead to severe progressive familial intrahepatic cholestasis. The substrates of BSEP are practically restricted to bile salts and their metabolites. It is, however, subject to inhibition by endogenous metabolites or by drugs. A sustained inhibition will lead to acquired cholestasis, which can end in liver injury