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141.
Christian Johannes Gloeckner Annette Schumacher Karsten Boldt† Marius Ueffing† 《Journal of neurochemistry》2009,109(4):959-968
Autosomal dominant mutations in the human Leucine-Rich Repeat Kinase 2 ( LRRK2 ) gene represent the most common monogenetic cause of Parkinson disease (PD) and increased kinase activity observed in pathogenic mutants of LRRK2 is most likely causative for PD-associated neurotoxicity. The sequence of the LRRK2 kinase domain shows similarity to MAP kinase kinase kinases. Furthermore, LRRK2 shares highest sequence homology with mixed linage kinases which act upstream of canonical MAPKK and are involved in cellular stress responses. Therefore, we addressed the question if LRRK2 exhibits MAPKKK activity by systematically testing MAPKKs as candidate substrates, in vitro . We demonstrate that LRRK2 variants phosphorylate mitogen-activated protein kinase kinases (MAPKK), including MKK3 -4, -6 and -7. MKKs act upstream of the MAPK p38 and JNK mediating oxidative cell stress, neurotoxicity and apoptosis. The disease-associated LRRK2 G2019S and I2020T mutations show an increased phosphotransferase activity towards MKKs correlating with the activity shown for its autophosphorylation. Our findings present evidence of a new class of molecular targets for mutant LRRK2 that link to neurotoxicity, cellular stress, cytoskeletal dynamics and vesicular transport. 相似文献
142.
Stefan Landgraeber Sandra Jaeckel Franz Löer Christian Wedemeyer Gero Hilken Ali Canbay Martin Totsch Marius von Knoch 《Apoptosis : an international journal on programmed cell death》2009,14(2):173-181
Particle-induced osteolysis is a major cause of aseptic loosening after total joint replacement. Earlier studies demonstrated
apoptotic macrophages, giant cells, fibroblasts and T-lymphocytes in capsules and interface membranes of patients with aseptic
hip implant loosening. The aim of the current study was to determine in a murine calvarial model of wear particle-induced
osteolysis whether inhibition of apoptosis using the pan-caspase inhibitor BOC-D-FMK reduces aseptic loosening. Healthy 12-week-old
male C57BL/6J mice were treated with UHMWPE particles and received a daily peritoneal injection of BOK-D-FMK, respectively
only buffer at a dose of 3 mg/kg of body weight for 12 days until sacrifice. Bone resorption was measured by histomorphometry,
micro CT (computed tomography) and TRAP-5b serum analysis. Apoptosis was measured using caspase-3 cleaved staining. The results
demonstrated that UHMWPE particles induced stronger apoptotic reactions in macrophages and osteoblasts and increased bone
resorption in non-specifically treated mice, whereas peritoneal application of BOC-D-FMK significantly counteracted these
adverse particle-related effects. We think that in particle-induced osteolysis apoptosis is pathologically increased, and
that failure to reduce the quantity of apoptotic bodies leads to an up-regulation of proinflammtory cytokines, which may be
responsible for the induction of osteolysis. We showed for the first time in vivo that a reduction in apoptosis leads to a
significant reduction in particle-induced osteolysis. Clinically, the apoptotic cascade could become an interesting novel
therapeutic target to modulate particle-induced osteolysis.
This is an investigation performed at the University of Duisburg-Essen, Germany. 相似文献
143.
144.
Marius Henriksen Jens Aaboe Erik B. Simonsen Tine Alkjær Henning Bliddal 《Journal of biomechanics》2009,42(9):1236-1240
Hip and knee functions are intimately connected and reduced hip abductor function might play a role in development of knee osteoarthritis (OA) by increasing the external knee adduction moment during walking. The purpose of this study was to test the hypothesis that reduced function of the gluteus medius (GM) muscle would lead to increased external knee adduction moment during level walking in healthy subjects. Reduced GM muscle function was induced experimentally, by means of intramuscular injections of hypertonic saline that produced an intense short-term muscle pain and reduced muscle function. Isotonic saline injections were used as non-painful control. Fifteen healthy subjects performed walking trials at their self-selected walking speed before and immediately after injections, and again after 20 min of rest, to ensure pain recovery. Standard gait analyses were used to calculate three-dimensional trunk and lower extremity joint kinematics and kinetics. Surface electromyography (EMG) of the glutei, quadriceps, and hamstring muscles were also measured. The peak GM EMG activity had temporal concurrence with peaks in frontal plane moments at both hip and knee joints. The EMG activity in the GM muscle was significantly reduced by pain (?39.6%). All other muscles were unaffected. Peaks in the frontal plane hip and knee joint moments were significantly reduced during pain (?6.4% and ?4.2%, respectively). Lateral trunk lean angles and midstance hip joint adduction and knee joint extension angles were reduced by ?1°. Thus, the gait changes were primarily caused by reduced GM function. Walking with impaired GM muscle function due to pain significantly reduced the external knee adduction moment. This study challenge the notion that reduced GM function due to pain would lead to increased loads at the knee joint during level walking. 相似文献
145.
146.
Virus-Induced Chaperone-Enriched (VICE) domains form adjacent to nuclear viral replication compartments (RC) during the early stages of HSV-1 infection. Between 2 and 3 hours post infection at a MOI of 10, host protein quality control machinery such as molecular chaperones (e.g. Hsc70), the 20S proteasome and ubiquitin are reorganized from a diffuse nuclear distribution pattern to sequestration in VICE domains. The observation that VICE domains contain putative misfolded proteins suggests that they may be similar to nuclear inclusion bodies that form under conditions in which the protein quality control machinery is overwhelmed by the presence of misfolded proteins. The detection of Hsc70 in VICE domains, but not in nuclear inclusion bodies, indicates that Hsc70 is specifically reorganized by HSV-1 infection. We hypothesize that HSV-1 infection induces the formation of nuclear protein quality control centers to remodel or degrade aberrant nuclear proteins that would otherwise interfere with productive infection. Detection of proteolytic activity in VICE domains suggests that substrates may be degraded by the 20S proteasome in VICE domains. FRAP analysis reveals that GFP-Hsc70 is dynamically associated with VICE domains, suggesting a role for Hsc70 in scanning the infected nucleus for misfolded proteins. During 42°C heat shock, Hsc70 is redistributed from VICE domains into RC perhaps to remodel viral replication and regulatory proteins that have become insoluble in these compartments. The experiments presented in this paper suggest that VICE domains are nuclear protein quality control centers that are modified by HSV-1 to promote productive infection. 相似文献
147.
Agricultural intensification caused a fragmentation of flower-rich extensively used meadows which resulted in the reduction
of the abundance of species of these habitats. The abundance pattern and the dispersal behaviour of species influence the
connectivity of local populations. In this context exchange rates can be directly measured by mark release recapture (MRR)
studies and indirectly by genetic analysis. Both approaches are used in our study in a comparative way. As a test species
to investigate the influence of habitat interconnectivity on a local and regional scale, we selected the butterfly Melanargia galathea (Lepidoptera, Nymphalidae), a widely distributed species, which is common on flower-rich meadows in our study area in western
Germany. We marked 3,175 individuals of four neighbouring sites in a mark-release-recapture study and analysed 18 allozyme
loci for 644 individuals sampled over 17 sites. Only 3.3% of the total genetic variance was found among samples, thus supporting
the detected between-patch movements. Both approaches revealed a high exchange rate among local populations. Moderate between-
and high within-patch movements were recorded by MRR analysis, dependent on the geographical distance. The two analytical
tools showed high estimated effective population sizes for all populations. In the light of conservation biology, the combination
of the MRR and allozyme data support the assumption that high dispersal ability and habitat interconnectivity countervail
genetic differentiation and enable the maintenance of a high level of genetic differentiation. 相似文献
148.
The human immunodeficiency virus type-1 (HIV-1) envelope (Env) proteins that mediate membrane fusion represent a major target for the development of new AIDS therapies. Three classes of Env-mediated membrane fusion inhibitors have been described that specifically target the pre-hairpin intermediate conformation of gp41. Class 2 inhibitors bind to the C-terminal heptad repeat (C-HR) of gp41. The single example of a class 3 inhibitor targets the trimeric N-terminal heptad repeat (N-HR) of gp41 and has been postulated to sequestrate the N-HR of the pre-hairpin intermediate through the formation of fusion incompetent heterotrimers. Here, we show that N(CCG)-gp41, a class 2 inhibitor, and N36(Mut(e,g)), a class 3 inhibitor, synergistically inhibit Env-mediated membrane fusion for several representative HIV-1 strains (X4 and R5) in both a cell fusion assay (with membrane-bound CD4) and an Env-pseudo-typed virus neutralization assay. The mechanistic, as well as potential therapeutic, implications of these observations for HIV-Env-mediated membrane fusion are discussed. 相似文献
149.
Salomon Kuizon Kathleen DiMaiuta Marius Walus Edmund C. Jenkins Jr Marisol Kuizon Elizabeth Kida Adam A. Golabek Daniel O. Espinoza Raju K. Pullarkat Mohammed A. Junaid 《PloS one》2010,5(8)
Background
Tripeptidyl aminopeptidase I (TPPI) is a crucial lysosomal enzyme that is deficient in the fatal neurodegenerative disorder called classic late-infantile neuronal ceroid lipofuscinosis (LINCL). It is involved in the catabolism of proteins in the lysosomes. Recent X-ray crystallographic studies have provided insights into the structural/functional aspects of TPPI catalysis, and indicated presence of an octahedrally coordinated Ca2+.Methodology
Purified precursor and mature TPPI were used to study inhibition by NBS and EDTA using biochemical and immunological approaches. Site-directed mutagenesis with confocal imaging technique identified a critical W residue in TPPI activity, and the processing of precursor into mature enzyme.Principal Findings
NBS is a potent inhibitor of the purified TPPI. In mammalian TPPI, W542 is critical for tripeptidyl peptidase activity as well as autocatalysis. Transfection studies have indicated that mutants of the TPPI that harbor residues other than W at position 542 have delayed processing, and are retained in the ER rather than transported to lysosomes. EDTA inhibits the autocatalytic processing of the precursor TPPI.Conclusions/Significance
We propose that W542 and Ca2+ are critical for maintaining the proper tertiary structure of the precursor proprotein as well as the mature TPPI. Additionally, Ca2+ is necessary for the autocatalytic processing of the precursor protein into the mature TPPI. We have identified NBS as a potent TPPI inhibitor, which led in delineating a critical role for W542 residue. Studies with such compounds will prove valuable in identifying the critical residues in the TPPI catalysis and its structure-function analysis. 相似文献150.
The 2010 Annual Meeting of the International Society for Stem Cell Research (ISSCR) was held in San Francisco in June with an exciting program covering a wealth of stem cell research from basic science to clinical research. 相似文献