Tau-Mediated Nuclear Depletion and Cytoplasmic Accumulation of SFPQ in Alzheimer's and Pick's Disease

Tau dysfunction characterizes neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Here, we performed an unbiased SAGE (serial analysis of gene expression) of differentially expressed mRNAs in the amygdala of transgenic pR5 mice that express human tau carrying the P301L mutation previously identified in familial cases of FTLD. SAGE identified 29 deregulated transcripts including Sfpq that encodes a nuclear factor implicated in the splicing and regulation of gene expression. To assess the relevance for human disease we analyzed brains from AD, Pick's disease (PiD, a form of FTLD), and control cases. Strikingly, in AD and PiD, both dementias with a tau pathology, affected brain areas showed a virtually complete nuclear depletion of SFPQ in both neurons and astrocytes, along with cytoplasmic accumulation. Accordingly, neurons harboring either AD tangles or Pick bodies were also depleted of SFPQ. Immunoblot analysis of human entorhinal cortex samples revealed reduced SFPQ levels with advanced Braak stages suggesting that the SFPQ pathology may progress together with the tau pathology in AD. To determine a causal role for tau, we stably expressed both wild-type and P301L human tau in human SH-SY5Y neuroblastoma cells, an established cell culture model of tau pathology. The cells were differentiated by two independent methods, mitomycin C-mediated cell cycle arrest or neuronal differentiation with retinoic acid. Confocal microscopy revealed that SFPQ was confined to nuclei in non-transfected wild-type cells, whereas in wild-type and P301L tau over-expressing cells, irrespective of the differentiation method, it formed aggregates in the cytoplasm, suggesting that pathogenic tau drives SFPQ pathology in post-mitotic cells. Our findings add SFPQ to a growing list of transcription factors with an altered nucleo-cytoplasmic distribution under neurodegenerative conditions

Cytoplasmic Accumulation and Aggregation of TDP-43 upon Proteasome Inhibition in Cultured Neurons

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterized by intraneuronal deposition of the nuclear TAR DNA-binding protein 43 (TDP-43) caused by unknown mechanisms. Here, we studied TDP-43 in primary neurons under different stress conditions and found that only proteasome inhibition by MG-132 or lactacystin could induce significant cytoplasmic accumulation of TDP-43, a histopathological hallmark in disease. This cytoplasmic accumulation was accompanied by phosphorylation, ubiquitination and aggregation of TDP-43, recapitulating major features of disease. Proteasome inhibition produced similar effects in both hippocampal and cortical neurons, as well as in immortalized motor neurons. To determine the contribution of TDP-43 to cell death, we reduced TDP-43 expression using small interfering RNA (siRNA), and found that reduced levels of TDP-43 dose-dependently rendered neurons more vulnerable to MG-132. Taken together, our data suggests a role for the proteasome in subcellular localization of TDP-43, and possibly in disease

Motives and comprehension in a public goods game with induced emotions

This study analyses the sensitivity of public goods contributions through the lens of psychological motives. We report the results of a public goods experiment in which subjects were induced with the motives of care and anger through autobiographical recall. Subjects' preferences, beliefs, and perceptions under each motive are compared with those of subjects experiencing a neutral autobiographical recall control condition. We find, but only for those subjects with the highest comprehension of the game, that care elicits significantly higher contributions than anger, with the control treatment in between. This positive influence of the care motive on unconditional giving is accounted for partly by preferences for giving and partly by the beliefs concerning greater contributions by others. Anger also affects attention to own and other's payoffs (using mouse tracking) and perceptions of the game's incentive structure (cooperative or competitive)

The formation of garnet in olivine-bearing metagabbros from the Adirondacks

A regional study of olivine-bearing metagabbros in the Adirondacks has permitted testing of the P(pressure)-T(temperature)-X(composition) dependence of garnet-forming reactions as well as providing additional regional metamorphic pressure data. Six phases, olivine, orthopyroxene, clinopyroxene, garnet, plagioclase and spinel, which can be related by the reactions: orthopyroxene+clinopyroxene+spinel +anorthite=garnet, and forsterite+anorthite=garnet occur together both in coronal and in equant textures indicative of equilibrium. Compositions of the respective minerals are typically Fo 25–72 , En 44–75 , En 30–44 Fs 9–23 Wo 47–49 , Pp 13–42 Alm 39–63 Gr 16–20 , An 29–49 and Sp 16–58 . When they occur in the same rock, equant and coronal garnets are homogeneous and compositionally identical suggesting that chemical equilibrium may have been attained despite coronal textures. Extrapolating reactions in the simple CMAS system to granulite temperatures and making thermodynamic corrections for solid solutions gives equilibration pressures (using the thermometry of Bohlen et al. 1980b) ranging from about 6.5 kb in the Lowlands and southern Adirondacks to 7.0–8.0 kb in the Highlands for the assemblage olivine-plagioclase-garnet. These results are consistent with inferred peak metamorphic conditions in the Adirondacks (Valley and Bohlen 1979; Bohlen and Boettcher 1981). Thus the isobaric retrograde path suggested by Whitney and McLelland (1973) and Whitney (1978) for the formation of coronal garnet in olivine metagabbros may not be required. Application of the same equilibria gives >8.7 kb for South Harris, Scotland and 0.9 kb for the Nain Complex. Disagreement of the latter value with orthopyroxeneolivine-quartz barometry (Bohlen and Boettcher 1981) suggests that the use of iron-rich rocks (olivines ≧Fa 50 ) results in errors in calculated pressures.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47335/1/410_2004_Article_BF00371301.pd

Designing biologic selectivity for inflammatory bowel disease – role of vedolizumab

Niklas Krupka, Daniel C Baumgart Division of Gastroenterology and Hepatology, Department of Medicine, Charité Medical School, Humboldt-University of Berlin, Berlin, Germany Abstract: Crohn’s disease and ulcerative colitis are two chronic inflammatory bowel conditions. Current approved biologic therapies are limited to blocking tumor necrosis factor alpha. Unfortunately, some patients are primary nonresponders, experiencing a loss of response, intolerance, or side effects. This defines an unmet need for novel therapeutic strategies. The rapid recruitment and inappropriate retention of leukocytes is a hallmark of chronic inflammation and a potentially promising therapeutic target. Here we discuss the clinical trial results of vedolizumab (anti-α4β7, LDP-02, MLN-02, and MLN0002) and its impact on future management of inflammatory bowel disease. Keywords: ulcerative colitis, Crohn’s disease, vedolizumab, MLN0002, MLN-02, LDP-02, anti-α4β

Will the original glucose transporter isoform please stand up!

Monosaccharides enter cells by slow translipid bilayer diffusion by rapid, protein-mediated, cation-dependent cotransport and by rapid, protein-mediated equilibrative transport. This review addresses protein-mediated, equilibrative glucose transport catalyzed by GLUT1, the first equilibrative glucose transporter to be identified, purified, and cloned. GLUT1 is a polytopic, membrane-spanning protein that is one of 13 members of the human equilibrative glucose transport protein family. We review GLUT1 catalytic and ligand-binding properties and interpret these behaviors in the context of several putative mechanisms for protein-mediated transport. We conclude that no single model satisfactorily explains GLUT1 behavior. We then review GLUT1 topology, subunit architecture, and oligomeric structure and examine a new model for sugar transport that combines structural and kinetic analyses to satisfactorily reproduce GLUT1 behavior in human erythrocytes. We next review GLUT1 cell biology and the transcriptional and posttranscriptional regulation of GLUT1 expression in the context of development and in response to glucose perturbations and hypoxia in blood-tissue barriers. Emphasis is placed on transgenic GLUT1 overexpression and null mutant model systems, the latter serving as surrogates for the human GLUT1 deficiency syndrome. Finally, we review the role of GLUT1 in the absence or deficiency of a related isoform, GLUT3, toward establishing the physiological significance of coordination between these two isoforms