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81.
Hiltunen M Lu A Thomas AV Romano DM Kim M Jones PB Xie Z Kounnas MZ Wagner SL Berezovska O Hyman BT Tesco G Bertram L Tanzi RE 《The Journal of biological chemistry》2006,281(43):32240-32253
Ubiquilin 1 (UBQLN1) is a ubiquitin-like protein, which has been shown to play a central role in regulating the proteasomal degradation of various proteins, including the presenilins. We recently reported that DNA variants in UBQLN1 increase the risk for Alzheimer disease, by influencing expression of this gene in brain. Here we present the first assessment of the effects of UBQLN1 on the metabolism of the amyloid precursor protein (APP). For this purpose, we employed RNA interference to down-regulate UBQLN1 in a variety of neuronal and non-neuronal cell lines. We demonstrate that down-regulation of UBQLN1 accelerates the maturation and intracellular trafficking of APP, while not interfering with alpha-, beta-, or gamma-secretase levels or activity. UBQLN1 knockdown increased the ratio of APP mature/immature, increased levels of full-length APP on the cell surface, and enhanced the secretion of sAPP (alpha- and beta-forms). Moreover, UBQLN1 knockdown increased levels of secreted Abeta40 and Abeta42. Finally, employing a fluorescence resonance energy transfer-based assay, we show that UBQLN1 and APP come into close proximity in intact cells, independently of the presence of the presenilins. Collectively, our findings suggest that UBQLN1 may normally serve as a cytoplasmic "gatekeeper" that may control APP trafficking from intracellular compartments to the cell surface. These findings suggest that changes in UBQLN1 steady-state levels affect APP trafficking and processing, thereby influencing the generation of Abeta. 相似文献
82.
The physiological period length of the human circadian clock in vivo is directly proportional to period in human fibroblasts 总被引:1,自引:0,他引:1
Pagani L Semenova EA Moriggi E Revell VL Hack LM Lockley SW Arendt J Skene DJ Meier F Izakovic J Wirz-Justice A Cajochen C Sergeeva OJ Cheresiz SV Danilenko KV Eckert A Brown SA 《PloS one》2010,5(10):e13376
Background
Diurnal behavior in humans is governed by the period length of a circadian clock in the suprachiasmatic nuclei of the brain hypothalamus. Nevertheless, the cell-intrinsic mechanism of this clock is present in most cells of the body. We have shown previously that for individuals of extreme chronotype (“larks” and “owls”), clock properties measured in human fibroblasts correlated with extreme diurnal behavior.Methodology/Principal Findings
In this study, we have measured circadian period in human primary fibroblasts taken from normal individuals and, for the first time, compared it directly with physiological period measured in vivo in the same subjects. Human physiological period length was estimated via the secretion pattern of the hormone melatonin in two different groups of sighted subjects and one group of totally blind subjects, each using different methods. Fibroblast period length was measured via cyclical expression of a lentivirally delivered circadian reporter. Within each group, a positive linear correlation was observed between circadian period length in physiology and in fibroblast gene expression. Interestingly, although blind individuals showed on average the same fibroblast clock properties as sighted ones, their physiological periods were significantly longer.Conclusions/Significance
We conclude that the period of human circadian behaviour is mostly driven by cellular clock properties in normal individuals and can be approximated by measurement in peripheral cells such as fibroblasts. Based upon differences among sighted and blind subjects, we also speculate that period can be modified by prolonged unusual conditions such as the total light deprivation of blindness. 相似文献83.
84.
Wnt/β-catenin signaling has a great and diverse influence on the formation, development, and vital activity of a great number of vertebrate tissues, including heart tissue. The role of Wnt/β-catenin signaling and β-catenin itself in the processes of cardiogenesis and adult myocardium functioning is not fully elucidated to date. The current review regards the attempt to generalize contemporary literature data on participation of this signaling pathway in embryogenesis and postnatal heart development, as well as in adult myocardium functioning in normal conditions and during stress adaptation, and aging, resulting in hypertrophy and heart remodeling. Based on the experimental articles and reviews, we can assume that Wnt/β-catenin signaling pathway is involved not only in controlling the cardiogenesis but also in processes of adaptation and remodeling of the adult organ. This control can be characterized as complicated and multistep and β-catenin appears to be a prospective candidate as a target for development of new approaches to adult myocardium pathologies therapy. 相似文献
85.
Karel Žák Martin Košťák Otakar Man Victor A. Zakharov Mikhail A. Rogov Petr Pruner Jan Rohovec Oksana S. Dzyuba Martin Mazuch 《Palaeogeography, Palaeoclimatology, Palaeoecology》2011,299(1-2):83-96
Carbon and oxygen stable isotope records were compared for Jurassic/Cretaceous (J/K) boundary sections located in the Tethyan Realm (Brodno, Western Slovakia, and Puerto Escaño, Southern Spain; bulk limestones), and the Boreal Realm (Nordvik Peninsula, Northern Siberia, belemnites). Since a detailed biostratigraphic correlation of these Tethyan and Boreal sections is impossible due to different faunal assemblages, correlation of the isotope records was based on paleomagnetic data. This novel approach can improve our understanding of the synchroneity of individual isotope excursions in sections where detailed biostratigraphic correlation is impossible. No significant excursions in either the carbon or oxygen isotope records to be used for future Boreal/Tethyan correlations were found around the J/K boundary (the upper Tithonian and lower Berriasian; magnetozones M20n to M18n) in the studied sections. At the Nordvik section, where a much longer section (middle Oxfordian–basal Boreal Berriasian) was documented, the transition from the middle Oxfordian to the Kimmeridgian and further to the Volgian is characterized by a decrease in belemnite δ18O values (from δ18O values up to + 1.6‰ vs. V-PDB in the Oxfordian to values between + 0.3 and ? 0.8‰ in the late Volgian and earliest Boreal Berriasian). This trend, which has previously been reported from the Russian Platform and Tethyan Realm sections, corresponds either to gradual warming or a decrease in seawater δ18O. Supposing that the oxygen isotope compositions of seawater in the Arctic/Boreal and Tethyan Realms were similar, then the differences between oxygen isotope datasets for these records indicate differences in temperature. The Boreal/Tethyan temperature difference of 7–9 °C in the middle and late Oxfordian decreases towards the J/K boundary, indicating a significant decrease in latitudinal climatic gradients during the Late Jurassic. Two positive carbon isotope excursions recorded for the middle Oxfordian and upper Kimmeridgian in the Nordvik section can be correlated with a similar excursion described earlier for the Russian Platform. Minor influence of biofractionation at the carbon isotopes, and the influence of migration of belemnites to deeper, slightly cooler water at the oxygen isotopes, cannot be excluded for the obtained belemnite data. 相似文献
86.
Ohki Y Higo T Uemura K Shimada N Osawa S Berezovska O Yokoshima S Fukuyama T Tomita T Iwatsubo T 《The EMBO journal》2011,30(23):4815-4824
Amyloid-β peptide ending at the 42nd residue (Aβ42) is implicated in the pathogenesis of Alzheimer's disease (AD). Small compounds that exhibit selective lowering effects on Aβ42 production are termed γ-secretase modulators (GSMs) and are deemed as promising therapeutic agents against AD, although the molecular target as well as the mechanism of action remains controversial. Here, we show that a phenylpiperidine-type compound GSM-1 directly targets the transmembrane domain (TMD) 1 of presenilin 1 (PS1) by photoaffinity labelling experiments combined with limited digestion. Binding of GSM-1 affected the structure of the initial substrate binding and the catalytic sites of the γ-secretase, thereby decreasing production of Aβ42, possibly by enhancing its conversion to Aβ38. These data indicate an allosteric action of GSM-1 by directly binding to the TMD1 of PS1, pinpointing the target structure of the phenylpiperidine-type GSMs. 相似文献
87.
Adler M Sweeney RE Hamilton TA Lockridge O Duysen EG Purcell AL Deshpande SS 《Cellular and molecular neurobiology》2011,31(6):909-920
Electrophysiological and ultrastructural studies were performed on phrenic nerve-hemidiaphragm preparations isolated from
wild-type and acetylcholinesterase (AChE) knockout (KO) mice to determine the compensatory mechanisms manifested by the neuromuscular
junction to excess acetylcholine (ACh). The diaphragm was selected since it is the primary muscle of respiration, and it must
adapt to allow for survival of the organism in the absence of AChE. Nerve-elicited muscle contractions, miniature endplate
potentials (MEPPs) and evoked endplate potentials (EPPs) were recorded by conventional electrophysiological techniques from
phrenic nerve-hemidiaphragm preparations isolated from 1.5- to 2-month-old wild-type (AChE+/+) or AChE KO (AChE−/−) mice. These recordings were chosen to provide a comprehensive assessment of functional alterations of the diaphragm muscle
resulting from the absence of AChE. Tension measurements from AChE−/− mice revealed that the amplitude of twitch tensions was potentiated, but tetanic tensions underwent a use-dependent decline
at frequencies below 70 Hz and above 100 Hz. MEPPs recorded from hemidiaphragms of AChE−/− mice showed a reduction in frequency and a prolongation in decay (37%) but no change in amplitude compared to values observed
in age-matched wild-type littermates. In contrast, MEPPs recorded from hemidiaphragms of wild-type mice that were exposed
for 30 min to the selective AChE inhibitor 5-bis(4-allyldimethyl-ammoniumphenyl)pentane-3-one (BW284C51) exhibited a pronounced
increase in amplitude (42%) and a more marked prolongation in decay (76%). The difference between MEPP amplitudes and decays
in AChE−/− hemidiaphragms and in wild-type hemidiaphragms treated with BW284C51 represents effective adaptation by the former to a high
ACh environment. Electron microscopic examination revealed that diaphragm muscles of AChE−/− mice had smaller nerve terminals and diminished pre- and post-synaptic surface contacts relative to neuromuscular junctions
of AChE+/+ mice. The morphological changes are suggested to account, in part, for the ability of muscle from AChE−/− mice to function in the complete absence of AChE. 相似文献
88.
Asada-Utsugi M Uemura K Noda Y Kuzuya A Maesako M Ando K Kubota M Watanabe K Takahashi M Kihara T Shimohama S Takahashi R Berezovska O Kinoshita A 《Journal of neurochemistry》2011,119(2):354-363
Sequential processing of amyloid precursor protein (APP) by β- and γ-secretase leads to the generation of amyloid-β (Aβ) peptides, which plays a central role in Alzheimer's disease pathogenesis. APP is capable of forming a homodimer through its extracellular domain as well as transmembrane GXXXG motifs. A number of reports have shown that dimerization of APP modulates Aβ production. On the other hand, we have previously reported that N-cadherin-based synaptic contact is tightly linked to Aβ production. In the present report, we investigated the effect of N-cadherin expression on APP dimerization and metabolism. Here, we demonstrate that N-cadherin expression facilitates cis-dimerization of APP. Moreover, N-cadherin expression led to increased production of Aβ as well as soluble APPβ, indicating that β-secretase-mediated cleavage of APP is enhanced. Interestingly, N-cadherin expression affected neither dimerization of C99 nor Aβ production from C99, suggesting that the effect of N-cadherin on APP metabolism is mediated through APP extracellular domain. We confirmed that N-cadherin enhances APP dimerization by a novel luciferase-complementation assay, which could be a platform for drug screening on a high-throughput basis. Taken together, our results suggest that modulation of APP dimerization state could be one of mechanisms, which links synaptic contact and Aβ production. 相似文献
89.
Rusyn I Asakura S Li Y Kosyk O Koc H Nakamura J Upton PB Swenberg JA 《DNA Repair》2005,4(10):1099-1110
Ethylene oxide (EO) is an important industrial chemical that is classified as a known human carcinogen (IARC, Group 1). It is also a metabolite of ethylene (ET), a compound that is ubiquitous in the environment and is the most used petrochemical. ET has not produced evidence of cancer in laboratory animals and is "not classifiable as to its carcinogenicity to humans" (IARC, Group 3). The mechanism of carcinogenicity of EO is not well characterized, but is thought to involve the formation of DNA adducts. EO is mutagenic in a variety of in vitro and in vivo systems, whereas ET is not. Apurinic/apyrimidinic sites (AP) that result from chemical or glycosylase-mediated depurination of EO-induced DNA adducts could be an additional mechanism leading to mutations and chromosomal aberrations. This study tested the hypothesis that EO exposure results in the accumulation of AP sites and induces changes in expression of genes for base excision DNA repair (BER). Male Fisher 344 rats were exposed to EO (100 ppm) or ET (40 or 3000 ppm) by inhalation for 1, 3 or 20 days (6h/day, 5 days a week). Animals were sacrificed 2h after exposure for 1, 3 or 20 days as well as 6, 24 and 72 h after a single-day exposure. Experiments were performed with tissues from brain and spleen, target sites for EO-induced carcinogenesis, and liver, a non-target organ. Exposure to EO resulted in time-dependent increases in N7-(2-hydroxyethyl)guanine (7-HEG) in brain, spleen, and liver and N7-(2-hydroxyethyl)valine (7-HEVal) in globin. Ethylene exposure also induced 7-HEG and 7-HEVal, but the numbers of adducts were much lower. No increase in the number of aldehydic DNA lesions, an indicator of AP sites, was detected in any of the tissues between controls and EO-, or ET-exposed animals, regardless of the duration or strength of exposure. EO exposure led to a 3-7-fold decrease in expression of 3-methyladenine-DNA glycosylase (Mpg) in brain and spleen in rats exposed to EO for 1 day. Expression of 8-oxoguanine DNA glycosylase, Mpg, AP endonuclease (Ape), polymerase beta (Pol beta) and alkylguanine methyltransferase were increased by 20-100% in livers of rats exposed to EO for 20 days. The only effects of ET on BER gene expression were observed in brain, where Ape and Pol beta expression were increased by less than 20% after 20 days of exposure to 3000 ppm. These data suggest that DNA damage induced by exposure to EO is repaired without accumulation of AP sites and is associated with biologically insignificant changes in BER gene expression in target organs. We conclude that accumulation of AP sites is not a likely primary mechanism for mutagenicity and carcinogenicity of EO. 相似文献
90.