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Biomedical subjects

M Geppert

Publications and source records attributed to M Geppert.

At least 37 records · Page 2Linked to original sources
PubMed1994

Synaptic targeting of rabphilin-3A, a synaptic vesicle Ca2+/phospholipid-binding protein, depends on rab3A/3C.

rab3A, a low molecular weight GTP-binding protein of synaptic vesicles with a putative function in synaptic vesicle docking, interacts in a GTP-dependent manner with rabphilin-3A, a peripheral membrane protein that binds Ca2+ and phospholipids. We now show that rabphilin-3A is an evolutionarily conserved synaptic vesicle protein that is attached to synaptic vesicle membranes via its N terminus and exhibits a heterogeneous distribution among synapses. In rab3A-deficient mice, rabphilin-3A is decreased in synapses belonging to neurons that primarily express rab3A and accumulates in the perikarya of these neurons. In contrast, neurons expressing significant levels of rab3C still contain normal levels of rabphilin-3A in a synaptic pattern, and rabphilin-3A binds rab3C in vitro. These results suggest that analogous to the membrane recruitment of raf by ras, rab3A and rab3C may function in recruiting rabphilin-3A to the synaptic vesicle membrane in a GTP-dependent manner.

Adaptor Proteins, Signal Transducing↗
PubMed1994

Functional properties of multiple synaptotagmins in brain.

At least four forms of synaptotagmin are expressed in neurons. Of these, synaptotagmin I has an essential function in mediating Ca(2+)-triggered neurotransmitter release at hippocampal synapses, but the functional implications of multiple synaptotagmins are unknown. Synaptotagmins I-III exhibit a strikingly differential distribution between synapses, with most neurons coexpressing either synaptotagmins I or II with III. Synaptotagmin IV is present uniformly throughout the brain at low levels. Synaptotagmins III and IV are both coexpressed with synaptotagmin I in hippocampal synapses, suggesting that these synaptotagmins are not functionally redundant. The first C2 domains of synaptotagmins I-III exhibit similar Ca2+ affinities in phospholipid-binding assays, whereas that of synaptotagmin IV is unable to bind Ca2+. All synaptotagmins tested bind the clathrin-adaptor protein AP-2 with high affinity. Our results suggest that different synaptotagmins serve distinct but overlapping functions in neuronal membrane traffic, with synaptotagmins I and II representing alternative Ca2+ sensors in exocytosis and all synaptotagmins functioning as AP-2 receptors in endocytosis.

Adaptor Proteins, Vesicular Transport↗
PubMed1994

[The value of colposcopy and portio biopsy in preventive examination].

133 patients attending the colposcopy-laser outpatient consultations were examined simultaneously by cytology, colposcopy and punch biopsy. A cone biopsy was taken 25 patients and one patient was hysterectomised later. A comparison between cytology and histology revealed 17.1% false negative smear results. Cytology and histology showed the same result in 84.6%. The highest percentage of high-grade dysplasia was found in colposcopy with signs of punctation and/or mosaicism. A similar diagnosis was achieved in 92.3% of cases comparing punch with cone biopsy. Simultaneous use of cytology, colposcopy and punch biopsy enables reliable diagnosis and follow-up of dysplastic lesions of the cervix. Besides, one can use punch biopsy as basic histology for local destructive manoeuvres such as laser vaporisation.

Biopsy↗
PubMed1993

Short-term synaptic plasticity is altered in mice lacking synapsin I.

Synapsin I, the major phosphoprotein of synaptic vesicles, is thought to play a central role in neurotransmitter release. Here we introduce a null mutation into the murine synapsin I gene by homologous recombination. Mice with no detectable synapsin I manifest no apparent changes in well-being or gross nervous system function. Thus, synapsin I is not essential for neurotransmitter release. Electrophysiology reveals that mice lacking synapsin I exhibit a selective increase in paired pulse facilitation, with no major alterations in other synaptic parameters such as long-term potentiation. In addition to potential redundant functions shared with other proteins, synapsin I in normal mice may function to limit increases in neurotransmitter release elicited by residual Ca2+ after an initial stimulus.

Animals↗
PubMed1993

Polypeptide composition of the alpha-latrotoxin receptor. High affinity binding protein consists of a family of related high molecular weight polypeptides complexed to a low molecular weight protein.

alpha-Latrotoxin is a vertebrate neurotoxin from black widow spider venom that causes massive neurotransmitter release. In order to gain insight into the mechanism of action of alpha-latrotoxin, we have studied alpha-latrotoxin-binding proteins from bovine and rat brain. Proteins purified by affinity chromatography on immobilized alpha-latrotoxin were investigated. Two sets of proteins were isolated: 1) three polypeptides of M(r) 79,000, 65,000, and 43,000 that were eluted from immobilized alpha-latrotoxin by increasing KCl concentrations in the presence of Ca2+, and 2) a family of related proteins ranging in molecular weight from 160,000 to 220,000 and a low molecular weight component of M(r) 29,000 that were eluted from immobilized alpha-latrotoxin only after removal of Ca2+. Amino acid sequences of these proteins demonstrated that all of these proteins represent novel proteins except for the M(r) 65,000 polypeptide, which is identical with synaptotagmin (Petrenko, A. G., Perin, M. S., Davletov, B. A., Ushkaryov, Y. A., Geppert, M., and Südhof, T. C. (1991) Nature 353, 65-68). Surprisingly, the M(r) 79,000 and 43,000 proteins were also found in tissues insensitive to alpha-latrotoxin action. Since these proteins do not bind 125I-alpha-latrotoxin with high affinity, their purification probably is not physiologically significant. On the other hand, the fractions containing the M(r) 160,000-220,000 and 29,000 polypeptides bound alpha-latrotoxin with high affinity. Sucrose gradient centrifugations and anion exchange chromatography suggested that most of the M(r) 160,000-220,000 proteins were complexed with the M(r) 29,000 protein. alpha-Latrotoxin binding correlated with the presence of the M(r) 160,000-220,000 proteins and M(r) 29,000 polypeptide, and alpha-latrotoxin formed stable complexes with the M(r) 160,000-220,000 proteins. Accordingly, the alpha-latrotoxin receptor consists of a high molecular weight protein (M(r) 160,000-220,000) that is complexed with one or several copies of an M(r) 29,000 polypeptide. In addition, the receptor is found in a less tight association with synaptotagmin but not with other polypeptides.

Amino Acid Sequence↗
PubMed1993

[Suspected abortion: morphologic aspects--value of histological examination of curettage specimen in suspected abortion and extra-uterine pregnancy].

Curettage specimens of 104 patients with clinically suspected abortion and unknown localization have been examined histologically. 50 patients with defined ectopic pregnancy, 51 patients with proved abortion and 50 patients with legal abortion had been used to compare with. In two cases syncytial cells could be proved histologically and by this an abortion could be verified. We could see decidually transformed endometrium in all cases with uncertain or certain formerly intrauterine localization of pregnancy. Opposite to this in ectopic pregnancy we could observe this only in 54 per cent. Summarizing our results in abortions as well as in ectopic pregnancies similar histologic findings could be seen.

Abortion, Induced↗
PubMed1993

Evaluation of steroid hormone receptors with respect to tumor cellularity.

The cellularity grade of 350 carcinomas of the breast was determined in retrospect, and from these results 3 corrective factors were established. After biochemically assessing the concentrations of estrogen and progesterone receptors, these were compared with tumor size, histological type and cellularity. As expected, ductal carcinomas showed higher average hormone receptor concentrations than lobular or medullary carcinomas. There was no evidence of a positive correlation between receptor concentration and cellularity grade. Many times, an initially negative receptor status in the lobular carcinomas with their relative paucity of cells was modified to a positive status. Accordingly, further possible therapeutic approaches should be discussed with respect to tumor cellularity.

Biomarkers, Tumor↗
PubMed1993

Relative properties and localizations of synaptic vesicle protein isoforms: the case of the synaptophysins.

Synaptophysins are abundant synaptic vesicle proteins present in two forms: synaptophysin, also referred to as synaptophysin I (abbreviated syp I), and synaptoporin, also referred to as synaptophysin II (abbreviated syp II). In the present study, the properties and localizations of syp I and syp II were investigated to shed light on their relative functions. Our results reveal that syp II, similar to syp I, is an abundant, N-glycosylated membrane protein that is part of a heteromultimeric complex in synaptic vesicle membranes. Cross-linking studies indicate that syp II is linked to a low-molecular-weight protein in this complex as has been observed before for syp I. Furthermore, after transfection into CHO cells, syp II, similar to syp I, is targeted to the receptor-mediated endocytosis pathway. Immunocytochemistry of rat brain sections reveals that syp II expression is highly heterogeneous, with high concentrations of syp II only in selected neuronal populations, whereas syp I is more homogeneously expressed in most nerve terminals. In general, nerve terminals expressing syp II also express syp I. In addition to high levels of syp II observed in selected neurons, a rostrocaudal gradient of syp II expression was observed in the cerebellar cortex. Immunoelectron microscopy confirmed that syp II is localized to synaptic vesicles. Immunoprecipitations of synaptic vesicles from rat brain with antibodies to syp I demonstrated that syp II is colocalized with syp I on the same vesicles. However, after detergent solubilization, no coimmunoprecipitations of the two proteins were observed, suggesting that they are not complexed with each other although they are on the same vesicles. Together our results demonstrate that syp I and syp II have similar properties and are present on the same synaptic vesicles but do not coassemble. The presence of the two proteins in the same nerve terminal suggests that they have similar but nonidentical functions and that the relative abundance of the two proteins may contribute to the functional heterogeneity of nerve terminals.

Animals↗
PubMed1993

Diagnosis and follow-up of atypical hyperplasia of corpus endometrium--a critical methodological investigation.

Within 5 years 181 patients were diagnosed with grade I and grade II atypical hyperplasia (AH) in the curettage material of 4193 specimens at the University Department of Gynecology and Obstetrics in Tübingen. In 62.6% of grade I and in 38.8% of grade II AH, concomitant endometrial polyps were observed, rarely cystic alterations as well. Especially with AH grade II, most polyps exhibited epithelial proliferation. Plurifocality and in situ residuals of AH were seen (grade I 38.5%, grade II 77.3%). In the same time period 345 endometrial carcinomas were found. Due to embedding techniques and the observation that only approximately 60% of the cavum uteri surface is reached via curettage, diagnostic security is quite limited. It has been published that women with AH have a higher risk of developing endometrial carcinoma. A control curettage after 6 months or a wide indication for hysterectomy is recommended after atypical endometrial hyperplasia has been demonstrated.

Adenocarcinoma↗
PubMed1992

Neurexins: synaptic cell surface proteins related to the alpha-latrotoxin receptor and laminin.

A family of highly polymorphic neuronal cell surface proteins, the neurexins, has been identified. At least two genes for neurexins exist. Each gene uses alternative promoters and multiple variably spliced exons to potentially generate more than a 100 different neurexin transcripts. The neurexins were discovered by the identification of one member of the family as the receptor for alpha-latrotoxin. This toxin is a component of the venom from black widow spiders; it binds to presynaptic nerve terminals and triggers massive neurotransmitter release. Neurexins contain single transmembrane regions and extracellular domains with repeated sequences similar to sequences in laminin A, slit, and agrin, proteins that have been implicated in axon guidance and synaptogenesis. An antibody to neurexin I showed highly concentrated immunoreactivity at the synapse. The polymorphic structure of the neurexins, their neural localization, and their sequence similarity to proteins associated with neurogenesis suggest a function as cell recognition molecules in the nerve terminal.

Amino Acid Isomerases↗
PubMed1992

[Infiltrating tubo-ovarian abscess in IUD-associated actinomycosis].

We report on a case of a 55-year old patient with a great adnexal tumour (10 x 5 x 8 cm), on the left side with infiltration of the bladder and the pelvis with recurring urinary retention in the kidney. Histological examination revealed an intrauterine device-associated actinomycosis. Following a 6-month high dose penicillin therapy, the abdominal hysterectomy with adnexectomy and partial resection of the bladder with new implantation of the ureter (Boari) was performed. The postoperative period was uneventful, the urogram normal.

Abscess↗
PubMed1992

Neurexins.

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Amino Acid Sequence↗
PubMed1992

Growth fraction in breast carcinoma determined by Ki-67 immunostaining: correlation with pathological and clinical variables.

The growth fractions (GF) of 151 mammary carcinomas were determined in situ by Ki-67 immunoperoxidase staining. A mean value of 14.6% Ki-67-positive tumor cells, with a standard deviation of 11.1, was found. Tumors of histological grades 1 and 2 had a mean GF of 13.1% which was significantly lower (p less than 0.05) than that of grade 3 tumors (mean GF 17.3%). The 14 patients in whom distant metastases appeared after primary staging had a significantly higher (p less than 0.05) GF (21.3%) than the other patients (13.9%). No significant correlation was found between GF and concentration of hormone receptors, lymph node status, tumor size, or patient's age. Our results suggest that immunostaining with Ki-67 could be used as an additional tool to detect breast carcinoma patients with a high risk of developing metastases.

Adenocarcinoma↗
PubMed1992

[Analysis of lymph node status and lymph node morphology in cervix cancer operated by the Wertheim-Meigs-Okabayashi method].

We evaluated in the histologic labor, of the Department of Obstetrics and Gynaecology of the Tübingen University 133 specimens of cervical carcinomas stages I and II operated on according to Wertheim-Meigs-Okabayashi. Topic of this analysis is lymph node status, concomitant alterations and lymphangiosis carcinomatosa. On the average 22.1 lymph nodes (1-58) have been removed. 12.8 per cent of cervical carcinomas had metastases, on the average 3 ones. 78.6 per cent of the metastases were localized in nondilymphatici interiliaci, 14.3 per cent in nodi iliaci communes. 5-year survival with metastases was 70.6 per cent, without 90.5 per cent. Over all a lymphangiosis carcinomatosa in 20.3 per cent was detectable. In 59.9 per cent of the lymph node metastases additionally a lymphangiosis carcinomatosa was present, on the contrary only 9.9 per cent of tumour-free ones. 5-year survival with lymphangiosis carcinomatosa was 70.4 per cent and 92.4 per cent without. Regressive changes, mostly as vacat fat, were observed in like the same percentage both in tumour positive and tumourfree lymph nodes.

Adenocarcinoma↗
PubMed1991

Binding of synaptotagmin to the alpha-latrotoxin receptor implicates both in synaptic vesicle exocytosis.

A vertebrate neurotoxin, alpha-latrotoxin, from black widow spider venom causes synaptic vesicle exocytosis and neurotransmitter release from presynaptic nerve terminals. Although the mechanism of action of alpha-latrotoxin is not known, it does require binding of alpha-latrotoxin to a high-affinity receptor on the presynaptic plasma membrane. The alpha-latrotoxin receptor seems to be exclusively at the presynaptic plasmamembrane. Here we report that the alpha-latrotoxin receptor specifically binds to a synaptic vesicle protein, synaptotagmin, and modulates its phosphorylation. Synaptotagmin is a synaptic vesicle-specific membrane protein that binds negatively charged phospholipids and contains two copies of a putative Ca(2+)-binding domain from protein kinase C (the C2-domain), suggesting a regulatory role in synaptic vesicle fusion. Our findings suggest that a physiological role of the alpha-latrotoxin receptor may be the docking of synaptic vesicles at the active zone. The direct interaction of the alpha-latrotoxin receptor with a synaptic vesicle protein also suggests a mechanism of action for this toxin in causing neurotransmitter release.

Animals↗
PubMed1991

Synaptotagmin II. A novel differentially distributed form of synaptotagmin.

Synaptotagmin is a synaptic vesicle membrane protein with properties suggestive of a role in synaptic vesicle exocytosis (Perin, M. S., Fried, V. A., Mignery, G. A., Jahn, R., and Südhof, T. C. (1990) Nature 345, 260-263). Here, we report the structure of a novel form of synaptotagmin named synaptotagmin II that is highly homologous to the originally described synaptotagmin, now referred to as synaptotagmin I. Synaptotagmins I and II exhibit the same overall structure, containing a small intravesicular sequence that is glycosylated, a single transmembrane region, and a large carboxyl-terminal cytoplasmic sequence that includes two copies of an internal repeat homologous to the regulatory region of protein kinase C. The homology between synaptotagmins I and II is not uniformly distributed across the molecule but is highest in their carboxyl-terminal regulatory repeats (88% sequence identity) and lowest in their amino-terminal intravesicular sequences (46% sequence identity). RNA blots demonstrate complementary patterns of expression for synaptotagmins I and II, with synaptotagmin I preferentially expressed in rostral, phylogenetically younger brain regions, and synaptotagmin II predominantly expressed in caudal, phylogenetically older brain regions. With this description of two forms of synaptotagmin, all major synaptic vesicle proteins implicated in membrane traffic have now been shown to be present in several isoforms with differential distributions, suggesting that this is a general organizational principle of the mammalian brain.

Amino Acid Sequence↗
PubMed1990

Glucocorticoid therapy obscures the diagnosis of cerebral lymphoma.

Neuropathological and radiographical findings of two patients with primary CNS B cell lymphoma are presented. Prior to computerized tomographic (CT)-guided stereotactic biopsy both patients had received glucocorticoid therapy which led to marked tumor regression on CT scans and transient improvement of neurological deficits. Despite careful targeting and serial sampling, multiple biopsy specimens examined cytologically, histologically and immunomorphologically showed nonspecific reactive astrogliosis and conspicuous perivascular infiltrates of T lymphocytes. A second biopsy performed after an interval of 2 and 8 weeks, respectively, and short-term discontinuation of dexamethasone therapy in one case, unequivocally established the diagnosis of Non-Hodgkin lymphoma. It is concluded that steroid therapy may obscure the bioptic diagnosis of cerebral lymphoma. In addition to the well-known antiedematous effect of glucocorticoids neuropathologists and neurosurgeons should be aware of a rapid and pronounced lymphodepletive action of steroids on malignant CNS lymphomas.

Astrocytes↗