University of Göttingen

About: University of Göttingen is a education organization based out in Göttingen, Germany. It is known for research contribution in the topics: Population & Gene. The organization has 43851 authors who have published 86318 publications receiving 3010295 citations. The organization is also known as: Georg-August-Universität Göttingen & Universität Göttingen.

Liquid–liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau

Abstract: The protein Tau aggregates into tangles in the brain of patients with Alzheimer's disease. In solution, however, Tau is intrinsically disordered, highly soluble, and binds to microtubules. It is still unclear what initiates the conversion from an innocuous phase of high solubility and functionality to solid-like neurotoxic deposits. Here, we show that the microtubule-binding repeats of Tau, which are lysine-rich, undergo liquid-liquid phase separation in solution. Liquid-liquid demixing causes molecular crowding of amyloid-promoting elements of Tau and drives electrostatic coacervation. Furthermore, we demonstrate that three-repeat and four-repeat isoforms of Tau differ in their ability for demixing. Alternative splicing of Tau can thus regulate the formation of Tau-containing membrane-less compartments. In addition, phosphorylation of Tau repeats promotes liquid-liquid phase separation at cellular protein conditions. The combined data propose a mechanism in which liquid droplets formed by the positively charged microtubule-binding domain of Tau undergo coacervation with negatively charged molecules to promote amyloid formation.Tau forms aggregates in the brains of Alzheimer patients. Here, the authors identify conditions, where the microtubule-binding repeats of Tau undergo a phosphorylation-dependent liquid-liquid phase separation, leading to molecular crowding in the formed Tau liquid droplets and characterize them by NMR and other biophysical methods.

Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy

Abstract: Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10−3. We found significant previously unidentified signals (P < 5 × 10−8) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.

Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels

Abstract: In heart failure (HF), Ca2+/calmodulin kinase II (CaMKII) expression is increased. Altered Na+ channel gating is linked to and may promote ventricular tachyarrhythmias (VTs) in HF. Calmodulin regulates Na+ channel gating, in part perhaps via CaMKII. We investigated effects of adenovirus-mediated (acute) and Tg (chronic) overexpression of cytosolic CaMKIIδC on Na+ current (INa) in rabbit and mouse ventricular myocytes, respectively (in whole-cell patch clamp). Both acute and chronic CaMKIIδC overexpression shifted voltage dependence of Na+ channel availability by –6 mV (P < 0.05), and the shift was Ca2+ dependent. CaMKII also enhanced intermediate inactivation and slowed recovery from inactivation (prevented by CaMKII inhibitors autocamtide 2–related inhibitory peptide [AIP] or KN93). CaMKIIδC markedly increased persistent (late) inward INa and intracellular Na+ concentration (as measured by the Na+ indicator sodium-binding benzofuran isophthalate [SBFI]), which was prevented by CaMKII inhibition in the case of acute CaMKIIδC overexpression. CaMKII coimmunoprecipitates with and phosphorylates Na+ channels. In vivo, transgenic CaMKIIδC overexpression prolonged QRS duration and repolarization (QT intervals), decreased effective refractory periods, and increased the propensity to develop VT. We conclude that CaMKII associates with and phosphorylates cardiac Na+ channels. This alters INa gating to reduce availability at high heart rate, while enhancing late INa (which could prolong action potential duration). In mice, enhanced CaMKIIδC activity predisposed to VT. Thus, CaMKII-dependent regulation of Na+ channel function may contribute to arrhythmogenesis in HF.

First-Row Transition Metal (De)Hydrogenation Catalysis Based On Functional Pincer Ligands.

Abstract: The use of 3d metals in de/hydrogenation catalysis has emerged as a competitive field with respect to “traditional” precious metal catalyzed transformations. The introduction of functional pincer ligands that can store protons and/or electrons as expressed by metal–ligand cooperativity and ligand redox-activity strongly stimulated this development as a conceptual starting point for rational catalyst design. This review aims at providing a comprehensive picture of the utilization of functional pincer ligands in first-row transition metal hydrogenation and dehydrogenation catalysis and related synthetic concepts relying on these such as the hydrogen borrowing methodology. Particular emphasis is put on the implementation and relevance of cooperating and redox-active pincer ligands within the mechanistic scenarios.

Contribution of small habitat fragments to conservation of insect communities of grassland–cropland landscapes

Abstract: Habitat destruction and fragmentation of remaining habitat are major threats to global biodiversity. In this paper, we drew upon data from grassland butterflies, legume- feeding herbivores and their parasitoids, and the interactions between rape pollen beetles and their parasitoids in the agricultural landscapes of Germany to explore the following issues: (1) the relative importance of small habitat fragments for the conservation of bio- diversity (in contrast to the prevailing arguments in favor of large fragments); (2) the disruption of interspecific interactions in fragmented habitats; and (3) the relative impor- tance of the spatial arrangement of habitat fragments in landscapes of different complexity. The percentage of polyphagous butterfly species and their abundance were higher in small than in large calcareous grassland fragments, showing the relative importance of the landscape surrounding habitat fragments for less specialized species. A landscape per- spective is also needed to explain why several small fragments supported more butterfly species (even when only endangered species were considered) than the same area composed of only one or two fragments. Analyses of insects on legumes showed trophic-level dif- ferences, in that species numbers of parasitoids, but not of herbivores, benefited from habitat subdivision in landscapes. As percentage of parasitism (i.e., the strength of ecological interactions) increased with fragment area, both the ''several small'' and ''single large'' strategies appeared to have merit. An intermediate-fragmentation strategy of habitat con- servation in human-dominated landscapes may combine the advantages. Small habitat frag- ments should be scattered enough to cover a range of geographical area wide enough to maximize beta diversity and the spreading of risk, but with large habitat fragments close enough to enable dispersal among fragments, to reduce the extinction probability of area- sensitive species, and to stabilize predator-prey interactions. Parasitism of rape pollen beetles exhibited a distinct edge effect: it was higher near the crop field edge, i.e., near the parasitoids' overwintering sites (such as grassy strips). How- ever, this was only true in landscapes dominated by annual crops; in landscapes with a high percentage of permanent noncrop area ( .20%), such edge effects disappeared, pre- sumably because of the high overall density of these parasitoids. These data indicate that spatial configuration is important to mitigate extinction risks when habitat availability in a landscape is low, whereas no effect will be observed when overall area of habitat is high.