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41.
Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes 总被引:17,自引:8,他引:17
Campuzano V; Montermini L; Lutz Y; Cova L; Hindelang C; Jiralerspong S; Trottier Y; Kish SJ; Faucheux B; Trouillas P; Authier FJ; Durr A; Mandel JL; Vescovi A; Pandolfo M; Koenig M 《Human molecular genetics》1997,6(11):1771-1780
Friedreich ataxia is a progressive neurodegenerative disorder caused by
loss of function mutations in the frataxin gene. In order to unravel
frataxin function we developed monoclonal antibodies raised against
different regions of the protein. These antibodies detect a processed 18
kDa protein in various human and mouse tissues and cell lines that is
severely reduced in Friedreich ataxia patients. By immunocytofluorescence
and immunocytoelectron microscopy we show that frataxin is located in
mitochondria, associated with the mitochondrial membranes and crests.
Analysis of cellular localization of various truncated forms of frataxin
expressed in cultured cells and evidence of removal of an N-terminal
epitope during protein maturation demonstrated that the mitochondrial
targetting sequence is encoded by the first 20 amino acids. Given the
shared clinical features between Friedreich ataxia, vitamin E deficiency
and some mitochondriopathies, our data suggest that a reduction in frataxin
results in oxidative damage.
相似文献
42.
Robinson PN Booms P Katzke S Ladewig M Neumann L Palz M Pregla R Tiecke F Rosenberg T 《Human mutation》2002,20(3):153-161
The Marfan syndrome (MFS) is a pleiotropic, autosomal dominant disorder of connective tissue with highly variable clinical manifestations including aortic dilatation and dissection, ectopia lentis, and a series of skeletal anomalies. Mutations in the gene for fibrillin-1 (FBN1) cause MFS, and at least 337 mainly unique mutations have been published to date. FBN1 mutations have been found not only in MFS but also in a range of connective tissue disorders collectively termed fibrillinopathies ranging from mild phenotypes, such as isolated ectopia lentis, to severe disorders including neonatal MFS, which generally leads to death within the first two years of life. The present article intends to provide an overview of mutations found in MFS and related disorders and to discuss potential genotype-phenotype correlations in MFS. 相似文献
43.
Summary A modified photometric method for the determination of phospholipase A activities which is based on a previously published reaction principle is described. The modified assay uses a lyophilized substrate emulsion rather than a freshly prepared phospholipid emulsion and a new chromogen (tribromohydroxybenzoic acid and 4-amino-antipyrine) with a high molar absorption coefficient (1,930 m2/mol at 546 nm, 2,900 m2/mol at 512 nm wavelength). The new test is more practicable with respect to pipetting volumes and incubation times. Preliminary results of a method evaluation indicate that the modified assay fulfills the usual criteria for clinical chemical enzyme measurements. 相似文献
44.
Dithiothreitol prevents age-associated decrease in oocyte/conceptus viability in vitro 总被引:2,自引:0,他引:2
The present study was designed to ascertain whether the negative effects on
reproductive potential of post-ovulatory ageing in vitro of oocytes can be
prevented by antioxidant therapy. Mouse metaphase II (MII) oocytes were
aged in vitro for 12 h prior to insemination in the presence of varying
concentrations of L-ascorbic acid, 6-methoxy-
2,5,7,8-tetramethylchromane-2-carboxylic acid (Trolox), L-cystine
dihydrochloride, ethylenediaminetetraacetic acid (EDTA), beta-
mercaptoethanol and DL-dithiothreitol (DTT). In-vitro ageing of oocytes was
associated with lower fertilization rate, higher proportion of concepti
exhibiting cellular fragmentation at 24 h post-insemination and lower
percentage of concepti reaching the blastocyst stage. Ascorbic acid, Trolox
and EDTA had no effect on cellular fragmentation or potential of oocytes
for development. However, the probability of an oocyte reaching the
blastocyst stage was decreased (P < or = or = 0.05) in oocytes incubated
in the presence of L-cystine (50 and 500 microM) and beta-mercaptoethanol
(5, 50 and 500 microM) when compared to control aged oocytes.
Age-associated cellular fragmentation at 24 h post-insemination was
partially prevented (P < or = 0.05) by incubating oocytes in the
presence of beta-mercaptoethanol (500 microM). DTT (50 and 500 microM)
increased (P < or = 0.05) fertilization rate and number of cells at 81 h
post-insemination to levels similar to those exhibited by control oocytes.
Furthermore, both age-associated fragmentation at 24 h post-insemination (P
< or = 0.05) and decreased potential of oocytes for development to the
blastocyst stage (P < or = 0.05) were prevented, at least in part, by
culturing oocytes in the presence of DTT (50 microM). Although the
mechanism by which DTT exerts its beneficial effects on aged oocytes
remains to be elucidated, it may protect oocytes by preventing oxidation of
free thiol groups and/or altering a redox-independent signalling pathway
that mediates cellular fragmentation and death.
相似文献
45.
The mechanisms of cell adhesion to the extracellular matrix (ECM) which are of fundamental importance for function, survival, and growth of cells involve the formation of focal adhesions to facilitate integrin signaling. Recently, it became evident that focal adhesions are not stable but move to enable cell migration and ECM formation. We examined the number, size, and dynamic behavior of focal adhesions in living MG-63 osteoblastic cells, which were cultured on titanium surfaces with different roughnesses and on stainless steel (SS). As a marker for focal adhesions we used GFP-tagged vinculin, a cytoskeletal protein. Focal adhesions were smaller on titanium and on SS than on collagen-coated glass coverslips. The corundum-blasted rough surface of titanium induced the smallest adhesions. On all the surfaces that we have tested, we observed a mobility of focal adhesions. On collagen-coated coverslips focal adhesions moved with a speed of 60 nm/min. The speed was reduced on titanium and still more restricted on SS. The topography did not affect the mobility of focal adhesions. We conclude that on the material surfaces that we have studied a reduced mobility of focal adhesions may strengthen the linkages between cell and ECM but impair the ability to dynamically organize and remodel the ECM. The results may have a great impact in the functional evaluation of tailored biomaterial surfaces for the application in tissue engineering. 相似文献
46.
Jacques Chappuis Igor A. Sherman A. Wilhelm Neumann 《Annals of biomedical engineering》1983,11(5):435-449
Measurements of the surface tension of articular cartilage and friction experiments were carried out to provide further evidence
in support of a new theory regarding the mechanism of friction in joints. To determine the surface tension of cartilage, contact
angle measurements were used in conjunction with the equation of state for interfacial tensions. The advancing contact angle
between saline drops and articular cartilage was found to be 100°±5°, indicating a highly hydrophobic surface. The corresponding
surface tension value was calculated to be 22.5 ergs/cm2. Friction of cartilage against hydrophobic surfaces is shown to be lower than the friction of cartilage against hydrophilic
surfaces. All these results further support the theory that lubrication by nonwetting drops occurs in joints and may be responsible
for the exceptional friction characteristics of the joints. 相似文献
47.
Somatic mutation processes at a human minisatellite 总被引:6,自引:3,他引:6
Germline instability at human minisatellites frequently involves complex
inter-allelic transfers of repeat units usually restricted to one end of
the repeat array and apparently regulated by flanking DNA. In contrast,
nothing is known about the structural basis of somatic instability at
minisatellites. An electrophoretic size-enrichment strategy was therefore
developed at minisatellite MS32 (D1S8) to enable rare abnormal-length
mutants to be detected, validated and quantitated in blood DNA by single
molecule PCR. Structural analysis of rare mutant alleles in blood revealed
simple deletions/duplications of repeat unit blocks located at random along
the tandem repeat array, a mode of mutation completely different from that
seen in sperm. Furthermore, allele-specific suppression of sperm
instability at MS32 did not affect somatic instability. These data suggest
that conversion-based minisatellite mutation in sperm is completely
germline-specific and most likely meiotic in origin. Somatic instability
appears to occur by a separate pathway involving replication slippage or,
more likely, intra-allelic unequal crossing over.
相似文献
48.
C57BL/6J (B6) and DBA/2J (D2) mice differ in maternal behavior and nest building, but previous observations on nest building appear to be contradictory. Lactating B6 females spent more time nest building than lactating D2 females [Physiol. Behav. 67 (1999) 599.]; however, pregnant D2 females have been reported to build better nests than pregnant B6 females [Physiol. Behav. 29 (1982) 153.]. To resolve this apparent discrepancy, virgin B6 and D2 females were mated, and the nest quality of nulligravid, primigravid and lactating primiparous females was compared between groups and with that of virgin females. There were no strain differences in the nest ratings of virgin or mated nulligravid females, nor did these groups differ within strains. Pregnant and lactating females of both strains built better nests than nonpregnant females. There was an increase in nest ratings in both strains on the day of parturition. The nest ratings of pregnant and lactating females were higher in B6 than D2 females. The largest strain differences were observed between pregnant B6 and D2 females. One hypothesis to account for these results is that females of these two strains differ in their levels of or sensitivity to hormones during pregnancy and parturition. 相似文献
49.
Zankl A Neumann L Ignatius J Nikkels P Schrander-Stumpel C Mortier G Omran H Wright M Hilbert K Bonafé L Spranger J Zabel B Superti-Furga A 《American journal of medical genetics. Part A》2005,(1):61-67
Platyspondylic lethal skeletal dysplasia (PLSD) Torrance type (PLSD-T) is a rare skeletal dysplasia characterized by platyspondyly, brachydactyly, and metaphyseal changes. Generally a perinatally lethal disease, a few long-term survivors have been reported. Recently, mutations in the carboxy-propeptide of type II collagen have been identified in two patients with PLSD-T, indicating that PLSD-T is a type 2 collagen-associated disorder. We studied eight additional cases of PLSD-T and found that all had mutations in the C-propeptide domain of COL2A1. The mutational spectrum includes missense, stop codon and frameshift mutations. All non-sense mutations were located in the last exon, where they would escape non-sense-mediated RNA-decay. We conclude that PLSD-T is caused by mutations in the C-propeptide domain of COL2A1, which lead to biosynthesis of an altered collagen chain (as opposed to a null allele). Similar mutations have recently been found to be the cause of spondyloperipheral dysplasia, a non-lethal dominant disorder whose clinical and radiographical features overlap those of the rare long-term survivors with PLSD-T. Thus, spondyloperipheral dysplasia and PLSD-T constitute a novel subfamily within the type II collagenopathies, associated with specific mutations in the C-propeptide domain and characterized by distinctive radiological features including metaphyseal changes and brachydactyly that set them apart from other type 2 collagenopathies associated with mutations in the triple-helical domain of COL2A1. The specific phenotype of C-propeptide mutations could result from a combination of diminished collagen fibril formation, toxic effects through the accumulation of unfolded collagen chains inside the chondrocytes, and alteration of a putative signaling function of the carboxy-propeptide of type 2 collagen. 相似文献
50.
Macrophages are immune cells that play a pivotal role in the detection and elimination of pathogenic microorganisms. Macrophages possess a variety of surface receptors devoted to the recognition of non-self by discriminating between host and pathogen-derived structures. Recognition of foreign microorganisms by the macrophage ultimately results in phagocytosis and the eventual destruction of microorganisms by lysosomal enzymes, toxic reactive oxygen and nitrogen intermediates, and/or nutrient deprivational mechanisms. However, protozoan parasites such as Toxoplasma gondii, Trypanosoma cruzi, and Leishmania spp., parasitize macrophages, utilizing them as a host cell for their growth, replication, and/or maintenance of their life cycles. The protozoan parasites of the genus Leishmania are unique in that their intracellular replication in the host is predominantly restricted to a single cell type, the macrophage. This review focuses on the cellular processes involved in macrophage-mediated host defense against protozoan parasites, from the initial host-parasite interactions that mediate recognition to the mechanisms employed by macrophages to destroy and eliminate the pathogen. As an example model system of experimental study, we describe in more more detail the cellular interactions between macrophages and the obligate intracellular parasite of mammalian macrophages, Leishmania spp. 相似文献