43 research outputs found

    Convergent genetic and expression data implicate immunity in Alzheimer's disease

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    Background Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics

    Regulation of neuronal differentiation by proteins associated with nuclear bodies.

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    Nuclear bodies are large sub-nuclear structures composed of RNA and protein molecules. The Survival of Motor Neuron (SMN) protein localizes to Cajal bodies (CBs) and nuclear gems. Diminished cellular concentration of SMN is associated with the neurodegenerative disease Spinal Muscular Atrophy (SMA). How nuclear body architecture and its structural components influence neuronal differentiation remains elusive. In this study, we analyzed the effects of SMN and two of its interaction partners in cellular models of neuronal differentiation. The nuclear 23 kDa isoform of Fibroblast Growth Factor - 2 (FGF-2(23)) is one of these interacting proteins - and was previously observed to influence nuclear bodies by destabilizing nuclear gems and mobilizing SMN from Cajal bodies (CBs). Here we demonstrate that FGF-2(23) blocks SMN-promoted neurite outgrowth, and also show that SMN disrupts FGF-2(23)-dependent transcription. Our results indicate that FGF-2(23) and SMN form an inactive complex that interferes with neuronal differentiation by mutually antagonizing nuclear functions. Coilin is another nuclear SMN binding partner and a marker protein for Cajal bodies (CBs). In addition, coilin is essential for CB function in maturation of small nuclear ribonucleoprotein particles (snRNPs). The role of coilin outside of Cajal bodies and its putative impacts in tissue differentiation are poorly defined. The present study shows that protein levels of nucleoplasmic coilin outside of CBs decrease during neuronal differentiation. Overexpression of coilin has an inhibitory effect on neurite outgrowth. Furthermore, we find that nucleoplasmic coilin inhibits neurite outgrowth independent of SMN binding revealing a new function for coilin in neuronal differentiation

    Dynamically Stable Legged Locomotion (September 1985-Septembers1989)

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    This report documents our work in exploring active balance for dynamic legged systems for the period from September 1985 through September 1989. The purpose of this research is to build a foundation of knowledge that can lead both to the construction of useful legged vehicles and to a better understanding of animal locomotion. In this report we focus on the control of biped locomotion, the use of terrain footholds, running at high speed, biped gymnastics, symmetry in running, and the mechanical design of articulated legs

    SMN inhibits FGF-2<sup>23</sup> activation of Nurr1-dependent transcription.

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    <p>In this reporter-gene assay, the effects of FGF-2<sup>23</sup>, Nurr1 and SMN on transcription driven from the Nurr1 monomer binding responsive element (NBRE) were assessed by transfection of neuroblastoma cells NB. For this purpose, expression vectors for each protein and the NBRE-Luc reporter were used. Empty vector pcDNA3.1 was employed as a FGF-2 expression negative control and pβ-gal as a negative control for SMN constructs. Full-length-SMN (SMN1-294) inhibits transcriptional activation mediated by FGF-2<sup>23</sup>, whereas coexpression of the SMN mutant protein SMN235-294 (without the N-terminal FGF-2<sup>23</sup>-binding sequence and comprising amino acid residues 235-294) did not exhibit an inhibitory effect. Data represent the mean ± SEM of the ratio of firefly to <i>Renilla</i> luciferase activity (Fluc/Rluc) for n = 3 experiments, each performed in quadruplicate. Results were analyzed using one-way ANOVA followed by Tukeýs posthoc test (means ± SEM; ***, p<0.001; *, p<0.05; compared with pcDNA3.1/pNurr1.</p

    Regulation of the SMN-interacting protein coilin.

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    <p>Neuroblastoma SK-N-BE(2) cells were differentiated for different periods with retinoic acid (5 µM), lysed by sonification in modified RIPA-buffer <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0082871#pone.0082871-Forthmann1" target="_blank">[7]</a> and analyzed by Western blot for coilin, SMN and α-Tubulin (A). (B) Endogenous coilin protein levels were decreased significantly to 52% after 72h of differentiation, (C) while SMN protein levels were increased non-significantly after the same time of differentiation. (D) Cells were treated with RA and stained with anti-SMN and anti-coilin antibodies. Coilin-positive (SMN-negative Cajal bodies), SMN-positive (nuclear gems) as well as coilin- and SMN-positive dots (SMN-positive CBs) in the nucleus of differentiated NB cells were counted and compared with a non-differentiated control. No significant changes of absolute numbers of these nuclear bodies were detected. (E) Intensity correlation analyses of coilin and SMN in the nucleus of differentiated cells were performed and compared to a non-differentiated control. No change in colocalization of coilin and SMN was detected (B, C: n = 7, means ± SEM; *, p<0.05; **, p<0.01; unpaired, two tailed t-test; D: control, n = 18; 24h RA, n = 13; 72h RA, n = 20; E: control, n = 20; 24h RA, n = 15; 72h RA, n = 22).</p

    Expression of coilin decreases neurite outgrowth.

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    <p>(A) PC12 cells were transfected with pEGFP or pCoilin-EGFP. After incubation in differentiation medium with nerve growth factor (NGF) for three days, neurite lengths were measured and their relative changes analyzed. (B) N-terminal EGFP-tagged wild-type and mutant coilin-constructs decreased the length of neurites significantly in the same experiment. For statistical evaluation, averaged relative neurite lengths of n>100 cells were compared, pooled from three individual experiments (means ± SEM; n.s.; A: **, p<0.01; Mann-Whitney test; B: n.s., non-significant; *, p<0.05; **, p<0.01; ***, p<0.001; Dunn’s test for comparison of multiple groups).</p
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