Simons, Mikael

[["dc.bibliographiccitation.firstpage","33"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Cell and Tissue Research"],["dc.bibliographiccitation.lastpage","47"],["dc.bibliographiccitation.volume","352"],["dc.contributor.author","Schneider, Anja"],["dc.contributor.author","Simons, Mikael"],["dc.date.accessioned","2019-07-09T11:39:48Z"],["dc.date.available","2019-07-09T11:39:48Z"],["dc.date.issued","2012"],["dc.description.abstract","The intercellular transfer of misfolded proteins has received increasing attention in various neurodegenerative diseases characterized by the aggregation of specific proteins, as observed in Alzheimer’s, Parkinson’s and Huntington’s disease. One hypothesis holds that intercellular dissemination of these aggregates within the central nervous system results in the seeded assembly of the cognate soluble protein in target cells, similar to that proposed for transmissible prion diseases. The molecular mechanisms underlying the intercellular transfer of these proteinaceous aggregates are poorly understood. Various transfer modes of misfolded proteins including continuous cell-cell contacts such as nanotubes, unconventional secretion or microvesicle/exosome-associated dissemination have been suggested. Cells can release proteins, lipids and nucleic acids by vesicular exocytosis pathways destined for horizontal transfer. Encapsulation into microvesicular/exosomal vehicles not only protects these molecules from degradation and dilution in the extracellular space but also facilitates delivery over large distances, e.g. within the blood flow or interstitial fluid. Specific surface ligands might allow the highly efficient and targeted uptake of these vesicles by recipient cells. In this review, we focus on the cell biology and function of neuronal microvesicles/exosomes and discuss the evidence for pathogenic intercellular protein transfer mediated by vesicular carriers."],["dc.identifier.doi","10.1007/s00441-012-1428-2"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10314"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/58038"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.publisher","Springer"],["dc.publisher.place","Berlin/Heidelberg"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Exosomes: vesicular carriers for intercellular communication in neurodegenerative disorders"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","937"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","The Journal of Cell Biology"],["dc.bibliographiccitation.lastpage","948"],["dc.bibliographiccitation.volume","172"],["dc.contributor.author","Trajkovic, K."],["dc.contributor.author","Dhaunchak, A. S."],["dc.contributor.author","Goncalves, J. T."],["dc.contributor.author","Wenzel, D."],["dc.contributor.author","Schneider, Anja"],["dc.contributor.author","Bunt, Gertrude"],["dc.contributor.author","Nave, K. A."],["dc.contributor.author","Simons, Mikael"],["dc.date.accessioned","2018-11-07T10:06:22Z"],["dc.date.available","2018-11-07T10:06:22Z"],["dc.date.issued","2006"],["dc.description.abstract","During vertebrate brain development, axons are enwrapped by myelin, an insulating membrane produced by oligodendrocytes. Neuron-derived signaling molecules are temporally and spatially required to coordinate oligodendrocyte differentiation. In this study, we show that neurons regulate myelin membrane trafficking in oligodendrocytes. In the absence of neurons, the major myelin membrane protein, the proteolipid protein (PLP), is internalized and stored in late endosomes/lysosomes (LEs/Ls) by a cholesterol-dependent and clathrin-independent endocytosis pathway that requires actin and the RhoA guanosine triphosphatase. Upon maturation, the rate of endocytosis is reduced, and a cAMP-dependent neuronal signal triggers the transport of PLP from LEs/Ls to the plasma membrane. These findings reveal a fundamental and novel role of LEs/Ls in oligodendrocytes: to store and release PLP in a regulated fashion. The release of myelin membrane from LEs/Ls by neuronal signals may represent a mechanism to control myelin membrane growth."],["dc.identifier.doi","10.1083/jcb.200509022"],["dc.identifier.isi","000235971900018"],["dc.identifier.pmid","16520383"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/39080"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Rockefeller Univ Press"],["dc.relation.issn","0021-9525"],["dc.title","Neuron to glia signaling triggers myelin membrane exocytosis from endosomal storage sites"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e1001577"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","PLoS Biology"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Aggarwal, Shweta"],["dc.contributor.author","Snaidero, Nicolas"],["dc.contributor.author","Paehler, Gesa"],["dc.contributor.author","Frey, Steffen"],["dc.contributor.author","Sanchez, Paula"],["dc.contributor.author","Zweckstetter, Markus"],["dc.contributor.author","Janshoff, Andreas"],["dc.contributor.author","Schneider, Anja"],["dc.contributor.author","Weil, Marie-Theres"],["dc.contributor.author","Schaap, Iwan Alexander Taco"],["dc.contributor.author","Goerlich, Dirk"],["dc.contributor.author","Simons, Mikael"],["dc.date.accessioned","2018-11-07T09:23:52Z"],["dc.date.available","2018-11-07T09:23:52Z"],["dc.date.issued","2013"],["dc.description.abstract","Rapid conduction of nerve impulses requires coating of axons by myelin. To function as an electrical insulator, myelin is generated as a tightly packed, lipid-rich multilayered membrane sheath. Knowledge about the mechanisms that govern myelin membrane biogenesis is required to understand myelin disassembly as it occurs in diseases such as multiple sclerosis. Here, we show that myelin basic protein drives myelin biogenesis using weak forces arising from its inherent capacity to phase separate. The association of myelin basic protein molecules to the inner leaflet of the membrane bilayer induces a phase transition into a cohesive mesh-like protein network. The formation of this protein network shares features with amyloid fibril formation. The process is driven by phenylalanine-mediated hydrophobic and amyloid-like interactions that provide the molecular basis for protein extrusion and myelin membrane zippering. These findings uncover a physicochemical mechanism of how a cytosolic protein regulates the morphology of a complex membrane architecture. These results provide a key mechanism in myelin membrane biogenesis with implications for disabling demyelinating diseases of the central nervous system."],["dc.description.sponsorship","ERC Starting Grant; German Research Foundation [SI 746/9-1, TRR43]"],["dc.identifier.doi","10.1371/journal.pbio.1001577"],["dc.identifier.fs","600727"],["dc.identifier.isi","000321042900005"],["dc.identifier.pmid","23762018"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/9108"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/29688"],["dc.notes.intern","Merged from goescholar"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.relation.issn","1545-7885"],["dc.relation.orgunit","Fakultät für Physik"],["dc.rights","CC BY-NC-ND 3.0"],["dc.rights.uri","http://creativecommons.org/licenses/by-nc-nd/3.0/"],["dc.title","Myelin Membrane Assembly Is Driven by a Phase Transition of Myelin Basic Proteins Into a Cohesive Protein Meshwork"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","55833"],["dc.bibliographiccitation.issue","53"],["dc.bibliographiccitation.journal","Journal of Biological Chemistry"],["dc.bibliographiccitation.lastpage","55839"],["dc.bibliographiccitation.volume","279"],["dc.contributor.author","Schneider, Anja"],["dc.contributor.author","Araújo, Gilda Wright"],["dc.contributor.author","Trajkovic, Katarina"],["dc.contributor.author","Herrmann, Martin M."],["dc.contributor.author","Merkler, Doron"],["dc.contributor.author","Mandelkow, Eva-Maria"],["dc.contributor.author","Weissert, Robert"],["dc.contributor.author","Simons, Mikael"],["dc.date.accessioned","2018-11-07T10:43:09Z"],["dc.date.available","2018-11-07T10:43:09Z"],["dc.date.issued","2004"],["dc.description.abstract","Axonal damage is a major morphological correlate and cause of permanent neurological deficits in patients with multiple sclerosis (MS), a multifocal, inflammatory and demyelinating disease of the central nervous system. Hyperphosphorylation and pathological aggregation of microtubule-associated protein tau is a common feature of many neurodegenerative diseases with axonal degeneration including Alzheimer's disease. We have therefore analyzed tau phosphorylation, solubility and distribution in the brainstem of rats with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Tau was hyperphosphorylated at several sites also phosphorylated in Alzheimer's disease and became partially detergent-insoluble in EAE brains. Morphological examination demonstrated accumulation of amorphous deposits of abnormally phosphorylated tau in the cell body and axons of neurons within demyelinating plaques. Hyperphosphorylation of tau was accompanied by up-regulation of p25, an activator of cyclin-dependent kinase 5. Phosphorylation of tau, activation of cdk5, and axonal pathology were significantly reduced when diseased rats were treated with prednisolone, a standard therapy of acute relapses in MS. Hyperphosphorylation of tau was not observed in a genetic or nutritional model of axonal degeneration or demyelination, suggesting that inflammation as detected in the brains of rats with EAE is the specific trigger of tau pathology. In summary, our data provide evidence that axonal damage in EAE and possibly MS is linked to tau pathology."],["dc.identifier.doi","10.1074/jbc.M409954200"],["dc.identifier.isi","000225960800106"],["dc.identifier.pmid","15494405"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/46980"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.notes.submitter","Najko"],["dc.relation.issn","0021-9258"],["dc.title","Hyperphosphorylation and aggregation of tau in experimental autoimmune encephalomyelitis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","143"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","The Journal of Cell Biology"],["dc.bibliographiccitation.lastpage","145"],["dc.bibliographiccitation.volume","213"],["dc.contributor.author","Schneider, Anja"],["dc.contributor.author","Simons, Mikael"],["dc.date.accessioned","2018-11-07T10:15:24Z"],["dc.date.available","2018-11-07T10:15:24Z"],["dc.date.issued","2016"],["dc.identifier.doi","10.1083/jcb.201604024"],["dc.identifier.isi","000375513900004"],["dc.identifier.pmid","27114496"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/40803"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Rockefeller Univ Press"],["dc.relation.issn","1540-8140"],["dc.relation.issn","0021-9525"],["dc.title","Catching filopodia: Exosomes surf on fast highways to enter cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.subtype","letter_note"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2874"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","The Journal of Neuroscience"],["dc.bibliographiccitation.lastpage","2882"],["dc.bibliographiccitation.volume","28"],["dc.contributor.author","Schneider, Anja"],["dc.contributor.author","Rajendran, Lawrence"],["dc.contributor.author","Honsho, Masanori"],["dc.contributor.author","Gralle, Matthias"],["dc.contributor.author","Donnert, Gerald"],["dc.contributor.author","Wouters, Fred S."],["dc.contributor.author","Hell, Stefan"],["dc.contributor.author","Simons, Mikael"],["dc.date.accessioned","2017-09-07T11:48:46Z"],["dc.date.available","2017-09-07T11:48:46Z"],["dc.date.issued","2008"],["dc.description.abstract","The flotillins/reggie proteins are associated with noncaveolar membrane microdomains and have been implicated in the regulation of a clathrin- and caveolin-independent endocytosis pathway. Endocytosis is required for the amyloidogenic processing of the amyloid precursor protein (APP) and thus to initiate the release of the neurotoxic beta-amyloid peptide (A beta), the major component of extracellular plaques found in the brains of Alzheimer's disease patients. Here, we report that small interference RNA-mediated downregulation of flotillin-2 impairs the endocytosis of APP, in both neuroblastoma cells and primary cultures of hippocampal neurons, and reduces the production of A beta. Similar to tetanus neurotoxin endocytosis, but unlike the internalization of transferrin, clathrin- dependent endocytosis of APP requires cholesterol and adaptor protein-2 but is independent of epsin1 function. Moreover, on a nanoscale resolution using stimulated emission depletion microscopy and by Forster resonance energy transfer with fluorescence lifetime imaging microscopy, we provide evidence that flotillin-2 promotes the clustering of APP at the cell surface. We show that the interaction of flotillin-2 with APP is dependent on cholesterol and that clustering of APP enhances its endocytosis rate. Together, our data suggest that cholesterol/flotillin-dependent clustering of APP may stimulate the internalization into a specialized clathrin-dependent endocytosis pathway to promote amyloidogenic processing."],["dc.identifier.doi","10.1523/JNEUROSCI.5345-07.2008"],["dc.identifier.gro","3143336"],["dc.identifier.isi","000253973600024"],["dc.identifier.pmid","18337418"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/839"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.issn","0270-6474"],["dc.title","Flotillin-dependent clustering of the amyloid precursor protein regulates its endocytosis and amyloidogenic processing in neurons"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Journal of Neurochemistry"],["dc.bibliographiccitation.lastpage","3"],["dc.bibliographiccitation.volume","120"],["dc.contributor.author","Schneider, Anja"],["dc.contributor.author","Simons, Mikael"],["dc.date.accessioned","2021-12-08T12:27:53Z"],["dc.date.available","2021-12-08T12:27:53Z"],["dc.date.issued","2011"],["dc.identifier.doi","10.1111/j.1471-4159.2011.07548.x"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/95484"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-476"],["dc.relation.issn","0022-3042"],["dc.rights.uri","http://doi.wiley.com/10.1002/tdm_license_1.1"],["dc.title","Antioxidative strategies in cognitive impairment: a novel connection between biliverdin-reductase and statins"],["dc.title.alternative","Review"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2415"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Journal of Cell Science"],["dc.bibliographiccitation.lastpage","2423"],["dc.bibliographiccitation.volume","118"],["dc.contributor.author","Schneider, Anja"],["dc.contributor.author","Lander, H."],["dc.contributor.author","Schulz, G."],["dc.contributor.author","Wolburg, Hartwig"],["dc.contributor.author","Nave, K. A."],["dc.contributor.author","Schulz, Joerg B."],["dc.contributor.author","Simons, Mikael"],["dc.date.accessioned","2018-11-07T10:43:55Z"],["dc.date.available","2018-11-07T10:43:55Z"],["dc.date.issued","2005"],["dc.description.abstract","Myelin is a specialized membrane enriched in glycosphingolipids and cholesterol that contains a restricted set of proteins. The mechanisms by which oligodendrocytes target myelin components to myelin are not known. To identify the sorting determinants for protein transport to myelin, we used a primary oligodendrocyte culture system in which terminal differentiation is synchronized and there is excessive deposition of myelin-like membranes (MLMs). Because several myelin proteins are palmitoylated, we explored the role of acylation in protein transport to MLMs. We found that palmitoylation-deficient mutants of a major myelin protein, proteolipid protein (PLP/DM20), were less efficiently targeted to MLMs. The N-terminal 13 amino acids of PLP/DM20, which are palmitoylated at three sites, were sufficient to direct a fluorescent fusion protein to MLMs. Mutagenesis of the N-terminal palmitoylation motif abolished the transport of the fusion protein to MLMs, indicating that palmitoylation is required for sorting to myelin. Similar results were obtained in myelinating co-cultures of oligodendrocytes and neurons. Furthermore, the combined farnesylation/palmitoylation signals from c-Ha-Ras and the N-terminal consensus sequence for dual palmitoylation from neuromodulin were sufficient for the transport of fluorescent fusion proteins to MLMs. Thus, we conclude that palmitoylation is a sorting determinant for transport to the myelin membrane."],["dc.identifier.doi","10.1242/jcs.02365"],["dc.identifier.isi","000230047500009"],["dc.identifier.pmid","15923654"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/47156"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Company Of Biologists Ltd"],["dc.relation.issn","0021-9533"],["dc.title","Palmitoylation is a sorting determinant for transport to the myelin membrane"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","26279"],["dc.bibliographiccitation.issue","34"],["dc.bibliographiccitation.journal","Journal of Biological Chemistry"],["dc.bibliographiccitation.lastpage","26288"],["dc.bibliographiccitation.volume","285"],["dc.contributor.author","Strauss, Katrin"],["dc.contributor.author","Goebel, Cornelia"],["dc.contributor.author","Runz, Heiko"],["dc.contributor.author","Möbius, Wiebke"],["dc.contributor.author","Weiss, Sievert"],["dc.contributor.author","Feussner, Ivo"],["dc.contributor.author","Simons, Mikael"],["dc.contributor.author","Schneider, Anja"],["dc.date.accessioned","2018-11-07T08:40:18Z"],["dc.date.available","2018-11-07T08:40:18Z"],["dc.date.issued","2010"],["dc.description.abstract","Niemann-Pick type C1 disease is an autosomal-recessive lysosomal storage disorder. Loss of function of the npc1 gene leads to abnormal accumulation of free cholesterol and sphingolipids within the late endosomal and lysosomal compartments resulting in progressive neurodegeneration and dysmyelination. Here, we show that oligodendroglial cells secrete cholesterol by exosomes when challenged with cholesterol or U18666A, which induces late endosomal cholesterol accumulation. Up-regulation of exosomal cholesterol release was also observed after siRNA-mediated knockdown of NPC1 and in fibroblasts derived from NPC1 patients and could be reversed by expression of wild-type NPC1. We provide evidence that exosomal cholesterol secretion depends on the presence of flotillin. Our findings indicate that exosomal release of cholesterol may serve as a cellular mechanism to partially bypass the traffic block that results in the toxic lysosomal cholesterol accumulation in Niemann-Pick type C1 disease. Furthermore, we suggest that secretion of cholesterol by exosomes contributes to maintain cellular cholesterol homeostasis."],["dc.identifier.doi","10.1074/jbc.M110.134775"],["dc.identifier.isi","000280921000045"],["dc.identifier.pmid","20554533"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/19200"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Amer Soc Biochemistry Molecular Biology Inc"],["dc.relation.issn","0021-9258"],["dc.title","Exosome Secretion Ameliorates Lysosomal Storage of Cholesterol in Niemann-Pick Type C Disease"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","5037"],["dc.bibliographiccitation.issue","21"],["dc.bibliographiccitation.journal","EMBO Journal"],["dc.bibliographiccitation.lastpage","5048"],["dc.bibliographiccitation.volume","25"],["dc.contributor.author","Fitzner, Dirk"],["dc.contributor.author","Schneider, Anja"],["dc.contributor.author","Kippert, Angelika"],["dc.contributor.author","Möbius, Wiebke"],["dc.contributor.author","Willig, Katrin I."],["dc.contributor.author","Hell, Stefan"],["dc.contributor.author","Bunt, Gertrude"],["dc.contributor.author","Gaus, Katharina"],["dc.contributor.author","Simons, Mikael"],["dc.date.accessioned","2017-09-07T11:52:27Z"],["dc.date.available","2017-09-07T11:52:27Z"],["dc.date.issued","2006"],["dc.description.abstract","During vertebrate development, oligodendrocytes wrap their plasma membrane around axons to produce myelin, a specialized membrane highly enriched in galactosylceramide (GalC) and cholesterol. Here, we studied the formation of myelin membrane sheets in a neuron-glia co-culture system. We applied different microscopy techniques to visualize lipid packing and dynamics in the oligodendroglial plasma membrane. We used the fluorescent dye Laurdan to examine the lipid order with two-photon microscopy and observed that neurons induce a dramatic lipid condensation of the oligodendroglial membrane. On a nanoscale resolution, using stimulated emission depletion and fluorescence resonance energy transfer microscopy, we demonstrated a neuronal-dependent clustering of GalC in oligodendrocytes. Most importantly these changes in lipid organization of the oligodendroglial plasma membrane were not observed in shiverer mice that do not express the myelin basic protein. Our data demonstrate that neurons induce the condensation of the myelin-forming bilayer in oligodendrocytes and that MBP is involved in this process of plasma membrane rearrangement. We propose that this mechanism is essential for myelin to perform its insulating function during nerve conduction."],["dc.identifier.doi","10.1038/sj.emboj.7601376"],["dc.identifier.gro","3143596"],["dc.identifier.isi","000242214900001"],["dc.identifier.pmid","17036049"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1128"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.issn","0261-4189"],["dc.title","Myelin basic protein-dependent plasma membrane reorganization in the formation of myelin"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]