Saftig, Paul

[["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Neurobiology of Aging"],["dc.bibliographiccitation.volume","23"],["dc.contributor.author","Vincent, B."],["dc.contributor.author","Paitel, E."],["dc.contributor.author","Lopez-Perez, E."],["dc.contributor.author","Checler, F."],["dc.contributor.author","Saftig, P."],["dc.contributor.author","Frobert, Y."],["dc.contributor.author","Grassi, J."],["dc.contributor.author","Hartmann, Daniel"],["dc.contributor.author","De Strooper, B."],["dc.date.accessioned","2018-11-07T10:23:17Z"],["dc.date.available","2018-11-07T10:23:17Z"],["dc.date.issued","2002"],["dc.format.extent","S70"],["dc.identifier.isi","000177465300261"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/42427"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Elsevier Science Inc"],["dc.publisher.place","New york"],["dc.relation.issn","0197-4580"],["dc.title","Physiological processing of the prion protein: Regulation by protein kinase c agonists and involvement of disintegrins"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Neurobiology of Aging"],["dc.bibliographiccitation.volume","23"],["dc.contributor.author","Hartmann, Daniel"],["dc.contributor.author","De Strooper, B."],["dc.contributor.author","Serneels, L."],["dc.contributor.author","Craessaerts, K."],["dc.contributor.author","Herreman, A."],["dc.contributor.author","Annaert, W."],["dc.contributor.author","Brabant, V."],["dc.contributor.author","Luebke, Torben"],["dc.contributor.author","Illert, A. L."],["dc.contributor.author","von Figura, Kurt"],["dc.contributor.author","Saftig, P."],["dc.date.accessioned","2018-11-07T10:23:07Z"],["dc.date.available","2018-11-07T10:23:07Z"],["dc.date.issued","2002"],["dc.format.extent","S183"],["dc.identifier.isi","000177465300670"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/42396"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Elsevier Science Inc"],["dc.publisher.place","New york"],["dc.relation.issn","0197-4580"],["dc.title","Deficiency for the disintegrin metalloprotease ADAM10 causes disturbed alpha-secretase function and a notch deficiency-related phenotype in mice"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2615"],["dc.bibliographiccitation.issue","21"],["dc.bibliographiccitation.journal","Human Molecular Genetics"],["dc.bibliographiccitation.lastpage","2624"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Hartmann, Daniel"],["dc.contributor.author","de Strooper, B."],["dc.contributor.author","Serneels, L."],["dc.contributor.author","Craessaerts, K."],["dc.contributor.author","Herreman, A."],["dc.contributor.author","Annaert, W."],["dc.contributor.author","Umans, L."],["dc.contributor.author","Lubke, T."],["dc.contributor.author","Illert, A. L."],["dc.contributor.author","von Figura, Kurt"],["dc.contributor.author","Saftig, P."],["dc.date.accessioned","2018-11-07T10:00:02Z"],["dc.date.available","2018-11-07T10:00:02Z"],["dc.date.issued","2002"],["dc.description.abstract","The metalloprotease ADAM 10 is an important APP alpha-secretase candidate, but in vivo proof of this is lacking. Furthermore, invertebrate models point towards a key role of the ADAM 10 orthologues Kuzbanian and sup-17 in Notch signalling. In the mouse, this function is, however, currently attributed to ADAM 17/TACE, while the role of ADAM 10 remains unknown. We have created ADAM 10-deficient mice. They die at day 9.5 of embryogenesis with multiple defects of the developing central nervous system, somites, and cardiovascular system. In situ hybridization revealed a reduced expression of the Notch target gene hes-5 in the neural tube and an increased expression of the Notch ligand dll-1, supporting an important role for ADAM 10 in Notch signalling in the vertebrates as well. Since the early lethality precluded the establishment of primary neuronal cultures, APPsalpha generation was analyzed in embryonic fibroblasts and found to be preserved in 15 out of 17 independently generated ADAM 10-deficient fibroblast cell lines, albeit at a quantitatively more variable level than in controls, whereas a severe reduction was found in only two cases. The variability was not due to differences in genetic background or to variable expression of the alternative a-secretase candidates ADAM 9 and ADAM 17. These results indicate, therefore, either a regulation between ADAMs on the post-translational level or that other, not yet known, proteases are able to compensate for ADAM 10 deficiency. Thus, the observed variability, together with recent reports on tissue-specific expression patterns of ADAMs 9, 10 and 17, points to the existence of tissue-specific 'teams' of different proteases exerting alpha-secretase activity."],["dc.identifier.doi","10.1093/hmg/11.21.2615"],["dc.identifier.isi","000178516000009"],["dc.identifier.pmid","12354787"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/37714"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Oxford Univ Press"],["dc.relation.issn","0964-6906"],["dc.title","The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","171"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Journal of Molecular Neuroscience"],["dc.bibliographiccitation.lastpage","181"],["dc.bibliographiccitation.volume","17"],["dc.contributor.author","Hartmann, Daniel"],["dc.contributor.author","Tournoy, J."],["dc.contributor.author","Saftig, P."],["dc.contributor.author","Annaert, W."],["dc.contributor.author","De Strooper, B."],["dc.date.accessioned","2018-11-07T08:36:21Z"],["dc.date.available","2018-11-07T08:36:21Z"],["dc.date.issued","2001"],["dc.description.abstract","Signaling via notch receptors and their ligands is an evolutionary ancient and highly conserved mechanism governing cell-fate decisions throughout the animal kingdom. Upon ligand binding, notch receptors are subject to a two-step proteolysis essential for signal transduction. First, the ectodomain is removed by an enzyme cleaving near the outer-membrane surface (\"site2\"). Consecutively, the notch intracellular domain is liberated by a second protease cutting within the transmembrane sequence (\"site3\"). The intracellular domain is then transferred to the nucleus to act as a transcriptional coactivator. The proteases involved in notch receptor activation are shared with other proteins undergoing regulated intramembrane proteolysis, with intriguing parallels to APP. Specifically, site3 cleavage of Notch, as well as gamma -secretase processing of APP depend both critically on presenilins 1 and 2. Moreover, ADAM 10 and ADAM 17, the proteases proposed to perform site2 cleavage, are also the most probable candidate alpha -secretases to cleave APP. While the biological significance of APP processing remains to be further elucidated, interference with notch signaling has been shown to have severe consequences both in small animal models as well as in humans. Thus a growing number of long known genetic syndromes like Alagille syndrome or Fallot's tetralogy can be caused by mutations of genes relevant for the notch signaling pathway. Likewise, the anticipated interference of gamma -secretase inhibitors with site3 cleavage may turn out to be a major obstacle for this therapeutic approach to Alzheimer's disease."],["dc.identifier.doi","10.1385/JMN:17:2:171"],["dc.identifier.isi","000172154800008"],["dc.identifier.pmid","11816790"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/18289"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Humana Press Inc"],["dc.relation.issn","0895-8696"],["dc.title","Implication of APP secretases in notch signaling"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","37743"],["dc.bibliographiccitation.issue","41"],["dc.bibliographiccitation.journal","Journal of Biological Chemistry"],["dc.bibliographiccitation.lastpage","37746"],["dc.bibliographiccitation.volume","276"],["dc.contributor.author","Vincent, B."],["dc.contributor.author","Paitel, E."],["dc.contributor.author","Saftig, P."],["dc.contributor.author","Frobert, Y."],["dc.contributor.author","Hartmann, Daniel"],["dc.contributor.author","De Strooper, B."],["dc.contributor.author","Grassi, J."],["dc.contributor.author","Lopez-Perez, E."],["dc.contributor.author","Checler, F."],["dc.date.accessioned","2018-11-07T08:32:34Z"],["dc.date.available","2018-11-07T08:32:34Z"],["dc.date.issued","2001"],["dc.description.abstract","We showed previously that PrPc undergoes constitutive and phorbol ester-regulated cleavage inside the 106-126 toxic domain of the protein, leading to the production of a fragment referred to as N1. Here we show by a pharmacological approach that o-phenanthroline, a general zinc-metalloprotease inhibitors, as well as BB3103 and TAPI, the inhibitors of metalloenzymes ADAM10 (A disintegrin and metalloprotease); and TACE, tumor necrosis factor alpha -converting enzyme; ADAM17), respectively, drastically reduce N1 formation. We set up stable human embryonic kidney 293 transfectants overexpressing human ADAM10 and TACE, and we demonstrate that ADAM10 contributes to constitutive N1 roduction whereas TACE mainly participates in regulated N1 formation. Furthermore, constitutive N1 secretion is drastically reduced in fibroblasts deficient for ADAM10 whereas phorbol 12,13-dibutyrate-regulated N1 production is fully abolished in TACE-deficient cells. Altogether, our data demonstrate for the first time that disintegrins could participate in the catabolism of glycosyl phosphoinositide-anchored proteins such as PrPc. Second, our study identifies ADAM10 and ADAM17 as the protease candidates responsible for normal cleavage of PrPc. Therefore, these disintegrins could be seen as putative cellular targets of a therapeutic strategy aimed at increasing normal PrPc breakdown and thereby depleting cells of the putative 106-126 \"toxic\" domain of PrPc."],["dc.identifier.isi","000171526500004"],["dc.identifier.pmid","11477090"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/17368"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Amer Soc Biochemistry Molecular Biology Inc"],["dc.relation.issn","0021-9258"],["dc.title","The disintegrins ADAM10 and TACE contribute to the constitutive and phorbol ester-regulated normal cleavage of the cellular prion protein"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","3132"],["dc.bibliographiccitation.issue","7"],["dc.bibliographiccitation.journal","Molecular Biology of the Cell"],["dc.bibliographiccitation.lastpage","3145"],["dc.bibliographiccitation.volume","15"],["dc.contributor.author","Eskelinen, E. L."],["dc.contributor.author","Schmidt, Christine K."],["dc.contributor.author","Neu, S."],["dc.contributor.author","Willenborg, M."],["dc.contributor.author","Fuertes, G."],["dc.contributor.author","Salvador, N."],["dc.contributor.author","Tanaka, Y."],["dc.contributor.author","Lullmann-Rauch, R."],["dc.contributor.author","Hartmann, Daniel"],["dc.contributor.author","Heeren, J."],["dc.contributor.author","von Figura, Kurt"],["dc.contributor.author","Knecht, E."],["dc.contributor.author","Saftig, P."],["dc.date.accessioned","2018-11-07T10:47:49Z"],["dc.date.available","2018-11-07T10:47:49Z"],["dc.date.issued","2004"],["dc.description.abstract","Mice double deficient in LAMP-1 and -2 were generated. The embryos died between embryonic days 14.5 and 16.5. An accumulation of autophagic vacuoles was detected in many tissues including endothelial cells and Schwann cells. Fibroblast cell lines derived from the double-deficient embryos accumulated autophagic vacuoles and the autophagy protein LC3II after amino acid starvation. Lysosomal vesicles were larger and more peripherally distributed and showed a lower specific density in Percoll gradients in double deficient when compared with control cells. Lysosomal enzyme activities, cathepsin D processing and mannose-6-phosphate receptor expression levels were not affected by the deficiency of both LAMPs. Surprisingly, LAMP-1 and -2 deficiencies did not affect long-lived protein degradation rates, including proteolysis due to chaperone-mediated autophagy. The LAMP-1/2 double-deficient cells and, to a lesser extent, LAMP-2 single-deficient cells showed an accumulation of unesterified cholesterol in endo/lysosomal, rab7, and NPC1 positive compartments as well as reduced amounts of lipid droplets. The cholesterol accumulation in LAMP-1/2 double-deficient cells could be rescued by overexpression of murine LAMP-2a, but not by LAMP-1, highlighting the more prominent role of LAMP-2. Taken together these findings indicate partially overlapping functions for LAMP-1 and -2 in lysosome biogenesis, autophagy, and cholesterol homeostasis."],["dc.identifier.doi","10.1091/mbc.E04-02-0103"],["dc.identifier.isi","000222333300013"],["dc.identifier.pmid","15121881"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/48052"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Amer Soc Cell Biology"],["dc.relation.issn","1059-1524"],["dc.title","Disturbed cholesterol traffic but normal proteolytic function in LAMP-1/LAMP-2 double-deficient fibroblasts"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","4899"],["dc.bibliographiccitation.issue","23"],["dc.bibliographiccitation.journal","Development"],["dc.bibliographiccitation.lastpage","4910"],["dc.bibliographiccitation.volume","128"],["dc.contributor.author","Suter, A."],["dc.contributor.author","Everts, V."],["dc.contributor.author","Boyde, A."],["dc.contributor.author","Jones, S. J."],["dc.contributor.author","Lullmann-Rauch, R."],["dc.contributor.author","Hartmann, Daniel"],["dc.contributor.author","Hayman, A. R."],["dc.contributor.author","Cox, T. M."],["dc.contributor.author","Evans, M. J."],["dc.contributor.author","Meister, T."],["dc.contributor.author","von Figura, Kurt"],["dc.contributor.author","Saftig, P."],["dc.date.accessioned","2018-11-07T11:20:43Z"],["dc.date.available","2018-11-07T11:20:43Z"],["dc.date.issued","2001"],["dc.description.abstract","To date, two lysosomal acid phosphatases are known to be expressed in cells of the monocyte/phagocyte lineage: the ubiquitously expressed lysosomal acid phosphatase (LAP) and the tartrate-resistant acid phosphatase-type 5 (Acp5). Deficiency of either acid phosphatase results in relatively mild phenotypes, suggesting that these enzymes may be capable of mutual complementation. This prompted us to generate LAP/Acp5 doubly deficient mice. LAP/Acp5 doubly deficient mice are viable and fertile but display marked alterations in soft and mineralised tissues. They are characterised by a progressive hepatosplenomegaly, gait disturbances and exaggerated foreshortening of long bones. Histologically, these animals are distinguished by an excessive lysosomal storage in macrophages of the liver, spleen, bone marrow, kidney and by altered growth plates. Microscopic analyses showed an accumulation of osteopontin adjacent to actively resorbing osteoclasts of Acp5- and LAP/Acp5-deficient mice. In osteoclasts of phosphatase-deficient mice, vacuoles were frequently found which contained fine filamentous material. The vacuoles in Acp5- and LAP/Acp5 doubly-deficient osteoclasts also contained crystallite-Iike features, as well as osteopontin, suggesting that Acp5 is important for processing of this protein. This is further supported by biochemical analyses that demonstrate strongly reduced dephosphorylation of osteopontin incubated with LAP/Acp5-deficient bone extracts. Fibroblasts derived from LAP/Acp5 deficient embryos were still able to dephosphorylate mannose 6-phosphate residues of endocytosed arylsulfatase A. We conclude that for several substrates LAP and Acp5 can substitute for each other and that these acid phosphatases are essential for processing of non-collagenous proteins, including osteopontin, by osteoclasts."],["dc.identifier.isi","000172740900022"],["dc.identifier.pmid","11731469"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/55608"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.relation.issn","0950-1991"],["dc.title","Overlapping functions of lysosomal acid phosphatase (LAP) and tartrate-resistant acid phosphatase (Acp5) revealed by doubly deficient mice"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","Acta Neuropathologica"],["dc.bibliographiccitation.volume","102"],["dc.contributor.author","Hartmann, Daniel"],["dc.contributor.author","de Strooper, B."],["dc.contributor.author","Serneels, L."],["dc.contributor.author","Craessaerts, K."],["dc.contributor.author","Herreman, A."],["dc.contributor.author","Annaert, W."],["dc.contributor.author","Lubke, T."],["dc.contributor.author","Junck, J."],["dc.contributor.author","Illert, A. L."],["dc.contributor.author","von Figura, Kurt"],["dc.contributor.author","Saftig, P."],["dc.date.accessioned","2018-11-07T11:24:42Z"],["dc.date.available","2018-11-07T11:24:42Z"],["dc.date.issued","2001"],["dc.format.extent","527"],["dc.identifier.isi","000171662200063"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/56465"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Springer"],["dc.publisher.place","New york"],["dc.relation.issn","0001-6322"],["dc.title","Deficiency for the disintegrin/metalloprotease ADAM 10 causes disturbed alpha secretase activity and a notch deficiency like phenotype in mice"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]