24 results on '"Shoichet, Sarah A."'
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2. Disease-associated synaptic scaffold protein CNK2 modulates PSD size and influences localisation of the regulatory kinase TNIK
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Zieger, Hanna L., Kunde, Stella-Amrei, Rademacher, Nils, Schmerl, Bettina, and Shoichet, Sarah A.
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- 2020
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3. Action of the Caenorhabditis elegans GATA Factor END-1 in Xenopus Suggests That Similar Mechanisms Initiate Endoderm Development in Ecdysozoa and Vertebrates
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Shoichet, Sarah A., Malik, Talat H., Rothman, Joel H., and Shivdasani, Ramesh A.
- Published
- 2000
4. Synaptic MAGUK Multimer Formation Is Mediated by PDZ Domains and Promoted by Ligand Binding
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Rademacher, Nils, Kunde, Stella-Amrei, Kalscheuer, Vera M., and Shoichet, Sarah A.
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- 2013
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5. Protein kinase C regulates AMPA receptor auxiliary protein Shisa9/CKAMP44 through interactions with neuronal scaffold PICK1
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Kunde, Stella‐Amrei, Rademacher, Nils, Zieger, Hanna, and Shoichet, Sarah A.
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- 2017
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6. Characterisation of de novo MAPK10/JNK3 truncation mutations associated with cognitive disorders in two unrelated patients
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Kunde, Stella-Amrei, Rademacher, Nils, Tzschach, Andreas, Wiedersberg, Eberhard, Ullmann, Reinhard, Kalscheuer, Vera M., and Shoichet, Sarah A.
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- 2013
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7. Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2
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Schmeisser, Michael J., Ey, Elodie, Wegener, Stephanie, Bockmann, Juergen, Stempel, A. Vanessa, Kuebler, Angelika, Janssen, Anna-Lena, Udvardi, Patrick T., Shiban, Ehab, Spilker, Christina, Balschun, Detlef, Skryabin, Boris V., tom Dieck, Susanne, Smalla, Karl-Heinz, Montag, Dirk, Leblond, Claire S., Faure, Philippe, Torquet, Nicolas, Le Sourd, Anne-Marie, Toro, Roberto, Grabrucker, Andreas M., Shoichet, Sarah A., Schmitz, Dietmar, Kreutz, Michael R., Bourgeron, Thomas, Gundelfinger, Eckart D., and Boeckers, Tobias M.
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Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour (1). Mutations in synaptic proteins such as neuroligins (2,3), neurexins (4), GKAPs/SAPAPs (5) and ProSAPs/ Shanks (6-10) were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/ Shanks build large homo- and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion (11,12). Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/[Shank.sup.-/-] mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced JV-methyl-D-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/[Shank.sup.-/-] mutants with ProSAP2/ Shank3α[β.sup.-/-] mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype., Many of the recently identified autism spectrum disorders (ASD) candidate genes code for proteins of excitatory synapses (13-15), suggesting that these disorders may arise from molecular imbalances of synaptic connections. [...]
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- 2012
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8. Mutations in autism susceptibility candidate 2 (AUTS2) in patients with mental retardation
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Kalscheuer, Vera M., FitzPatrick, David, Tommerup, Niels, Bugge, Merete, Niebuhr, Erik, Neumann, Luitgard M., Tzschach, Andreas, Shoichet, Sarah A., Menzel, Corinna, Erdogan, Fikret, Arkesteijn, Ger, Ropers, Hans-Hilger, and Ullmann, Reinhard
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- 2007
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9. A novel X-linked recessive mental retardation syndrome comprising macrocephaly and ciliary dysfunction is allelic to oral–facial–digital type I syndrome
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Budny, Bartlomiej, Chen, Wei, Omran, Heymut, Fliegauf, Manfred, Tzschach, Andreas, Wisniewska, Marzena, Jensen, Lars R., Raynaud, Martine, Shoichet, Sarah A., Badura, Magda, Lenzner, Steffen, Latos-Bielenska, Anna, and Ropers, Hans-Hilger
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- 2006
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10. Truncation of the CNS-expressed JNK3 in a patient with a severe developmental epileptic encephalopathy
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Shoichet, Sarah A., Duprez, Laurence, Hagens, Olivier, Waetzig, Vicki, Menzel, Corinna, Herdegen, Thomas, Schweiger, Susann, Dan, Bernard, Vamos, Esther, Ropers, Hans-Hilger, and Kalscheuer, Vera M.
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- 2006
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11. Haploinsufficiency of novel FOXG1B variants in a patient with severe mental retardation, brain malformations and microcephaly
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Shoichet, Sarah A., Kunde, Stella-Amrei, Viertel, Petra, Schell-Apacik, Can, von Voss, Hubertus, Tommerup, Niels, Ropers, Hans-Hilger, and Kalscheuer, Vera M.
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- 2005
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12. Mutations in the ZNF41 gene are associated with cognitive deficits: identification of a new candidate for X-linked mental retardation
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Shoichet, Sarah A., Hoffmann, Kirsten, Menzel, Corinna, Trautmann, Udo, Moser, Bettina, Hoeltzenbein, Maria, Echenne, Bernard, Partington, Michael, van Bokhoven, Hans, Moraine, Claude, Fryns, Jean-Peirre, Chelly, Jamel, Rott, Hans-Dieter, Ropers, Hans-Hilger, and Kalscheuer, Vera M.
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Human genetics -- Research ,Mental retardation -- Research ,Biological sciences - Published
- 2003
13. The synaptic scaffold protein MPP2 interacts with GABAA receptors at the periphery of the postsynaptic density of glutamatergic synapses.
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Schmerl, Bettina, Gimber, Niclas, Kuropka, Benno, Stumpf, Alexander, Rentsch, Jakob, Kunde, Stella-Amrei, von Sivers, Judith, Ewers, Helge, Schmitz, Dietmar, Freund, Christian, Schmoranzer, Jan, Rademacher, Nils, and Shoichet, Sarah A.
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SCAFFOLD proteins ,DENDRITIC spines ,CELL adhesion molecules ,SYNAPSES ,MEMBRANE proteins ,NEURAL transmission - Abstract
Recent advances in imaging technology have highlighted that scaffold proteins and receptors are arranged in subsynaptic nanodomains. The synaptic membrane-associated guanylate kinase (MAGUK) scaffold protein membrane protein palmitoylated 2 (MPP2) is a component of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor–associated protein complexes and also binds to the synaptic cell adhesion molecule SynCAM 1. Using superresolution imaging, we show that—like SynCAM 1—MPP2 is situated at the periphery of the postsynaptic density (PSD). In order to explore MPP2-associated protein complexes, we used a quantitative comparative proteomics approach and identified multiple γ-aminobutyric acid (GABA)
A receptor subunits among novel synaptic MPP2 interactors. In line with a scaffold function for MPP2 in the assembly and/or modulation of intact GABAA receptors, manipulating MPP2 expression had effects on inhibitory synaptic transmission. We further show that GABAA receptors are found together with MPP2 in a subset of dendritic spines and thus highlight MPP2 as a scaffold that serves as an adaptor molecule, linking peripheral synaptic elements critical for inhibitory regulation to central structures at the PSD of glutamatergic synapses. This study shows that the MAGUK scaffold protein MPP2 is located at the periphery of postsynaptic densities in excitatory neurons, where it interacts with GABA-A receptors, thereby serving as a functional adaptor that links excitatory and inhibitory components of synaptic transmission at glutamatergic synapses. [ABSTRACT FROM AUTHOR]- Published
- 2022
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14. Frataxin promotes antioxidant defense in a thiol-dependent manner resulting in diminished malignant transformation in vitro
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Shoichet, Sarah A., Bäumer, Anselm T., Stamenkovic, Djordje, Sauer, Heinrich, Pfeiffer, Andreas F. H., Kahn, C. Ronald, Müller-Wieland, Dirk, Richter, Christoph, and Ristow, Michael
- Published
- 2002
15. Protein kinase C regulates AMPA receptor auxiliary protein Shisa9/ CKAMP44 through interactions with neuronal scaffold PICK1.
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Kunde, Stella-Amrei, Rademacher, Nils, Zieger, Hanna, and Shoichet, Sarah A.
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PROTEIN kinase C ,PHOSPHORYLATION ,REGULATION of neural transmission ,SYNAPSES ,MOLECULAR neurobiology - Abstract
Synaptic α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate ( AMPA) receptors are essential mediators of neurotransmission in the central nervous system. Shisa9/cysteine-knot AMPAR modulating protein 44 ( CKAMP44) is a transmembrane protein recently found to be present in AMPA receptor-associated protein complexes. Here, we show that the cytosolic tail of Shisa9/ CKAMP44 interacts with multiple scaffold proteins that are important for regulating synaptic plasticity in central neurons. We focussed on the interaction with the scaffold protein PICK1, which facilitates the formation of a tripartite complex with the protein kinase C ( PKC) and thereby regulates phosphorylation of Shisa9/ CKAMP44 C-terminal residues. This work has implications for our understanding of how PICK1 modulates AMPAR-mediated transmission and plasticity and also highlights a novel function of PKC. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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16. Identification and characterisation of genes involved in cognitive function
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Shoichet, Sarah A.
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ZNF41 ,JNK3 ,chromosome abnormality ,brain ,genes ,mental retardation ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit ,cognitive function - Abstract
Title Page and Table of Contents 1\. Introduction 4 2\. Materials and Methods 18 3\. Results 36 4\. Discussion 70 5\. Summary 89 6\. Zusammenfassung 91 7\. Outlook 93 References 95 Abbreviations 105 List of Figures 108 List of Tables 109 Acknowledgements 110 Publications 113, In this study we have characterised the chromosome breakpoints in five patients with mental disabilities and associated balanced translocations, with the aim of identifying both X-chromosomal and autosomal genes critical for cognitive function. In light of the established link between mental disability and X-chromosomal genes, together with the practical advantages of studies that involve the X chromosome, we first focussed on patients with X;autosome translocations. In two out of three patients, molecular analyses provided no evidence for disease-causing gene disruptions on the X chromosome. In Patient 3, however, with a severe phenotype, the zinc finger gene ZNF41 was disrupted, and full-length transcripts could not be detected in the patient cell line, suggesting an absence of functional ZNF41 protein. Studies on unrelated families with X-linked mental retardation (XLMR) led to the identification of two novel nucleotide exchanges in the ZNF41 gene that likely play a role in the disease, based on their absence in 400 X chromosomes from controls. One of these mutations results in a proline to leucine amino acid exchange (P111L); the second is an intronic mutation (479-42A>C) that affects a consensus splice-site and results in loss of transcription of specific ZNF41 splice variants in the patient cell line. Both of these point mutations are associated with mild MR. The ZNF41 gene is expressed in multiple tissues, including both foetal and adult brain, and it has been implicated in transcriptional repression. Other ubiquitously expressed genes, namely the methyl CpG binding protein encoded by MECP2 and the helicase-encoding ATRX, have also been implicated in both mental retardation and regulation of transcription. Although it is not yet understood how mutations in these three genes exert brain-specific effects, it is conceivable that in neurons, their functions converge on a common critical pathway. In light of our results, ZNF41 is an especially strong novel candidate for XLMR. Rearrangements in two additional patients with severe cognitive disabilities and associated autosome translocations were also investigated as part of this study. Molecular cytogenetic analyses indicated the presence of well-characterised candidate genes in the vicinity of the breakpoints for both cases: in Patient 4, the brain-specific forkhead transcription factor FOXG1B, and in Patient 5, the predominantly CNS-expressed c-Jun terminal kinase gene JNK3. More precise localisation of the relevant breakpoints indicated that FOXG1B was not disrupted; JNK3, however, was interrupted within the coding sequence. For this reason, further studies focussed on JNK3. JNK3 plays an established role in neuronal apoptosis, and it has recently been shown to directly influence neuronal differentiation. The breakpoint results in translation of a truncated JNK3 protein, which could be detected by western blot in the patient cell line. Over-expression of this mutant protein in various cell lines, including HeLa and Neuro2A, led to protein aggregation, whereas over-expressed wild type JNK3 exhibited diffuse localisation, suggesting that the mutant plays an aberrant role in patient cells. We speculate that the severe neurological phenotype observed in Patient 5 results from a partial loss of JNK3 function in neurite outgrowth, together with a dominant effect on normal GTPase- mediated signalling through JNK3, which could result in modified regulation of neuronal apoptosis. This provides a plausible explanation for the severe phenotype observed in the patient. Taken together, our results affirm that making use of disease-associated balanced translocations remains an efficient approach for identifying candidate disease genes. In studying five patients, we have uncovered two promising candidate genes for mental retardation, and through both in silico and molecular studies have obtained further evidence for their respective roles in cognition. Moreover, our data support the recent hypothesis that both precise control of chromatin remodelling and fine regulation of GTPase-mediated signalling are essential for normal development and function of the brain., In der vorliegenden Arbeit wurden die chromosomalen Bruchpunkte bei fünf mental retardierten Patienten und einer balancierten Translokation untersucht, um sowohl X-chromosomale als auch autosomale Gene zu finden, die für kognitive Funktionen bedeutsam sein könnten. Basierend auf dem bereits bekannten Zusammenhang zwischen X-chromosomalen Genen und mentaler Retardierung und den praktischen Vorteilen von Untersuchungen am X-Chromosom wurden zunächst drei Patientinnen mit einer X;Autosom-Translokation untersucht. Die molekulare Charakterisierung ergab für zwei dieser drei Patientinnen keinerlei Hinweise auf einen Zusammenhang zwischen mentaler Retardierung und dem X-chromosomalen Bruchpunkt. Hingegen konnte in der dritten Patientin, die den ausgeprägtesten Phänotyp aufweist, eine Unterbrechung des Zink-Finger 41 (ZNF41) Gens nachgewiesen werden. Diese Unterbrechung hatte zur Folge, dass ein vollständiges Transkript des ZNF41 Gens in einer Zelllinie der Patientin nicht nachweisbar war, welches nahelegt, dass ein funktionelles ZNF41 Protein ebenfalls fehlt. Die Analyse von ZNF41 in nicht verwandten Familien mit X-chromosomal vererbter mentaler Retardierung (XLMR) führte zur Identifizierung von zwei Basenaustauschen, welche sehr wahrscheinlich krankheitsrelevant sind, da sie in 400 Kontrollchromosomen nicht gefunden werden konnten. Eine der Mutationen verursacht den Austausch eines Prolins durch ein Leucin (P111L) im ZNF41 Protein. Die andere Mutation befindet sich am Exon-Intron-Übergang und beeinträchtigt eine konservierte Spleissstelle (479-42A>C). Hieraus resultiert der Verlust einer spezifischen Spleissvariante von ZNF41 in der Zelllinie des Patienten. Beide Mutationen führten zu einer vergleichsweise milden mentalen Retardierung. Das ZNF41 Gen wird in vielen Geweben exprimiert, inklusive im fötalen und adulten Hirn, und ist an der molekularen Repression der Transkription beteiligt. Ein derartiger Zusammenhang zwischen mentaler Retardierung und Transkriptionsregulation wurde bereits für andere ubiquitär exprimierte Gene gezeigt, wie z.B. für das Methyl-CpG-bindende Protein 2 Gen MECP2, oder für das Helicase-kodierende Gen ATRX. Zusammen mit diesen Daten erscheint das ZNF41 Gen als besonders relevanter, neuer Kandidat für die genetische Grundlage der mentalen Retardierung. Im Rahmen dieser Arbeit wurden ebenfalls zwei Patienten mit schwerer mentaler Retardierung und einer autosomalen Translokation untersucht. Die molekular cytogenetischen Untersuchungen zeigten zunächst, dass bei beiden Patienten ein bereits detailliert charakterisiertes Kandidatengen im Bruchpunktbereich vorliegt: bei einer Patientin das hirnspezifisch exprimierte Forkhead-Transkriptionsfaktor FOXG1B Gen, bei dem anderen Patienten das überwiegend im Gehirn exprimierte C-Jun-N-terminale Kinase 3 (JNK3) Gen. Eine genauere, sequenzbasierte Analyse dieser beiden Bruchstellen ergab, dass das FOXG1B-Gen intakt vorlag, während das JNK3-Gen direkt unterbrochen war. Alle weiteren Untersuchungen konzentrierten sich daher auf JNK3. JNK3 spielt eine bekannte Rolle in der Regulation der neuronalen Apoptose, und wurde kürzlich mit einem direkten Einfluss auf die Differenzierung neuronaler Strukturen in Zusammenhang gebracht. Der Bruchpunkt im JNK3 Gen führt zu der Expression eines trunkierten JNK3 Proteins in der lymphoblastoiden Zelllinie des Patienten. Die Überexpression einer derartigen JNK3 Mutante in verschiedenen Zelllinien, einschliesslich HeLa and Neuro2A, zeigte eine Aggregation des trunkierten Proteins, während die Kontroll-Überexpression eines Wildtyp- JNK3-Proteins dieses Verhalten nicht aufzeigte. Zusammengenommen lässt dies annehmen, dass die Expression eines trunkierten JNK3 Proteins im Menschen zu einer aberranten, intrazellulären Aggregation dieses Proteins führt. Dies lässt vermuten, dass der ausgeprägte neurologische Phänotyp des Patienten aus einem partiellen JNK3 Funktionsverlust beim Neuritenwachstum und einem dominanten Effekt des trunkierten JNK3 Proteins auf die normale GTPase- vermittelte Signalübertragung resultiert. Dieser Mechanismus stellt eine plausible Erklärung für den beobachteten, schweren Phänotyp des Patienten dar. Zusammengefasst legen die vorgenannten Daten nahe, dass die Analyse von krankheitsassoziierten balancierten Translokationen einen effizienten Ansatz darstellen, Kandidatengene zu identifizieren. Durch die Untersuchung von fünf Indexpatienten konnten im Rahmen dieser Arbeit zwei neue Kandidatengene für die mentale Retardierung gefunden werden. Die mögliche Bedeutung dieser Gene wurde durch mutationsanalytische und molekularbiologische Methoden untermauert. Drittens unterstützen die Ergebnisse die kürzlich aufgestellten Hypothesen, dass sowohl die Kontrolle des Chromatinumbaus, als auch die Feinregulation der GTPase-vermittelten Signalübertragung eine essentielle Rolle in der normalen Entwicklung und Funktion des menschlichen Gehirns spielen.
- Published
- 2004
17. Identification of candidate genes for sporadic amyotrophic lateral sclerosis by array comparative genomic hybridization.
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Shoichet, Sarah A., Waibel, Stefan, Endruhn, Sonja, Sperfeld, Anne D., Vorwerk, Brita, Müller, Ines, Erdogan, Fikret, Ludolph, Albert C., Ropers, Hans-Hilger, and Ullmann, Reinhard
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AMYOTROPHIC lateral sclerosis , *CENTRAL nervous system diseases , *MOTOR neurons , *MEDICAL genetics , *NUCLEIC acid hybridization , *COMPARATIVE genomic hybridization , *ETIOLOGY of diseases , *PHYSIOLOGY - Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating disorder of the central nervous system that leads to progressive loss of upper and lower motor neurons. Most cases are sporadic and of unknown aetiology. In this study, we screened 72 patients with sporadic ALS for the presence of DNA copy number variations, in order to identify novel candidate disease genes. We have used sub-megabase resolution BAC array comparative genomic hybridization to detect genomic imbalances in our ALS patient cohort. Aberrations with potential relevance for disease aetiology were verified by oligo array CGH. In 72 patients with sporadic ALS, we identified a total of six duplications and five deletions that scored above our threshold. Nine of these 11 variations were smaller than 1Mb, and five were observed exclusively in ALS patients. In conclusion, non-polymorphic sub-microscopic duplications and deletions observable by array CGH are frequent in patients with sporadic ALS. Analysis of such aberrations serves as a starting point in deciphering the aetiology of this complex disease, given that affected genes can be considered candidates for influencing disease susceptibility. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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18. Transcriptional repression and developmental functions of the atypical vertebrate GATA protein TRPS1.
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Malik, Talat H., Shoichet, Sarah A., Latham, Peter, Kroll, Todd G., Peters, Luanne L., and Shivdasani, Ramesh A.
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GATA proteins , *ZINC-finger proteins , *NUCLEAR proteins , *VERTEBRATES , *HUMAN genes , *XENOPUS - Abstract
Known vertebrate GATA proteins contain two zinc fingers and are required in development, whereas invertebrates express a class of essential proteins containing one GATA‐type zinc finger. We isolated the gene encoding TRPS1, a vertebrate protein with a single GATA‐type zinc finger. TRPS1 is highly conserved between Xenopus and mammals, and the human gene is implicated in dominantly inherited tricho‐rhino‐phalangeal (TRP) syndromes. TRPS1 is a nuclear protein that binds GATA sequences but fails to transactivate a GATA‐dependent reporter. Instead, TRPS1 potently and specifically represses transcriptional activation mediated by other GATA factors. Repression does not occur from competition for DNA binding and depends on a C‐terminal region related to repressive domains found in Ikaros proteins. During mouse development, TRPS1 expression is prominent in sites showing pathology in TRP syndromes, which are thought to result from TRPS1 haploinsufficiency. We show instead that truncating mutations identified in patients encode dominant inhibitors of wild‐type TRPS1 function, suggesting an alternative mechanism for the disease. TRPS1 is the first example of a GATA protein with intrinsic transcriptional repression activity and possibly a negative regulator of GATA‐dependent processes in vertebrate development. [ABSTRACT FROM AUTHOR]
- Published
- 2001
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19. Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation.
- Author
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Freude, Kristine, Sefiani, Abdelaziz, Hoffmann, Kirsten, Moser, Bettina, Haas, Stefan, Gurok, Ulf, Haesler, Sebastian, Aranda, Beatriz, Nshedjan, Arpik, Tzschach, Andreas, Hartmann, Nils, Roloff, Tim-Christoph, Shoichet, Sarah, Hagens, Olivier, Jiong Tao, Olivier, Turner, Gillian, Chelly, Jamel, Moraine, Claude, Fryns, Jean-Pierre, and Kalscheuer, Vera M.
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GENETIC disorders ,X-linked intellectual disabilities ,GENETIC mutation ,CARRIER proteins ,GENES ,DEVELOPMENTAL disabilities - Abstract
We found mutations in the gene PQBP1 in 5 of 29 families with nonsyndromic (MRX) and syndromic (MRXS) forms of X-linked mental retardation (XLMR). Clinical features in affected males include mental retardation, microcephaly, short stature, spastic paraplegia and midline defects. PQBP1 has previously been implicated in the pathogenesis of polyglutamine expansion diseases. Our findings link this gene to XLMR and shed more light on the pathogenesis of this common disorder. [ABSTRACT FROM AUTHOR]
- Published
- 2003
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20. Sub-membrane actin rings compartmentalize the plasma membrane.
- Author
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Rentsch, Jakob, Bandstra, Selle, Sezen, Batuhan, Sigrist, Philipp, Bottanelli, Francesca, Schmerl, Bettina, Shoichet, Sarah, Noé, Frank, Sadeghi, Mohsen, and Ewers, Helge
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TOROIDAL plasma , *CELL membranes , *ACTIN , *MEMBRANE proteins , *ARTIFICIAL membranes , *ION channels , *COMPUTATIONAL neuroscience , *IMMUNOCOMPUTERS - Abstract
The compartmentalization of the plasma membrane (PM) is a fundamental feature of cells. The diffusivity of membrane proteins is significantly lower in biological than in artificial membranes. This is likely due to actin filaments, but assays to prove a direct dependence remain elusive. We recently showed that periodic actin rings in the neuronal axon initial segment (AIS) confine membrane protein motion between them. Still, the local enrichment of ion channels offers an alternative explanation. Here we show, using computational modeling, that in contrast to actin rings, ion channels in the AIS cannot mediate confinement. Furthermore, we show, employing a combinatorial approach of single particle tracking and super-resolution microscopy, that actin rings are close to the PM and that they confine membrane proteins in several neuronal cell types. Finally, we show that actin disruption leads to loss of compartmentalization. Taken together, we here develop a system for the investigation of membrane compartmentalization and show that actin rings compartmentalize the PM. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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21. MPP2 is a postsynaptic MAGUK scaffold protein that links SynCAM1 cell adhesion molecules to core components of the postsynaptic density.
- Author
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Rademacher, Nils, Schmerl, Bettina, Lardong, Jennifer A., Wahl, Markus C., and Shoichet, Sarah A.
- Published
- 2016
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22. The synaptic scaffold protein MPP2 interacts with GABAA receptors at the periphery of the postsynaptic density of glutamatergic synapses.
- Author
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Schmerl B, Gimber N, Kuropka B, Stumpf A, Rentsch J, Kunde SA, von Sivers J, Ewers H, Schmitz D, Freund C, Schmoranzer J, Rademacher N, and Shoichet SA
- Subjects
- Receptors, AMPA metabolism, Receptors, GABA-A, Synapses metabolism, Membrane Proteins metabolism, Post-Synaptic Density metabolism
- Abstract
Recent advances in imaging technology have highlighted that scaffold proteins and receptors are arranged in subsynaptic nanodomains. The synaptic membrane-associated guanylate kinase (MAGUK) scaffold protein membrane protein palmitoylated 2 (MPP2) is a component of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-associated protein complexes and also binds to the synaptic cell adhesion molecule SynCAM 1. Using superresolution imaging, we show that-like SynCAM 1-MPP2 is situated at the periphery of the postsynaptic density (PSD). In order to explore MPP2-associated protein complexes, we used a quantitative comparative proteomics approach and identified multiple γ-aminobutyric acid (GABA)A receptor subunits among novel synaptic MPP2 interactors. In line with a scaffold function for MPP2 in the assembly and/or modulation of intact GABAA receptors, manipulating MPP2 expression had effects on inhibitory synaptic transmission. We further show that GABAA receptors are found together with MPP2 in a subset of dendritic spines and thus highlight MPP2 as a scaffold that serves as an adaptor molecule, linking peripheral synaptic elements critical for inhibitory regulation to central structures at the PSD of glutamatergic synapses., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2022
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23. Intramolecular domain dynamics regulate synaptic MAGUK protein interactions.
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Rademacher N, Kuropka B, Kunde SA, Wahl MC, Freund C, and Shoichet SA
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- Animals, COS Cells, Chlorocebus aethiops, HEK293 Cells, Hippocampus cytology, Humans, Protein Binding, Protein Conformation, Protein Domains, Adaptor Proteins, Signal Transducing metabolism, Disks Large Homolog 4 Protein chemistry, Disks Large Homolog 4 Protein metabolism, GTP-Binding Protein beta Subunits metabolism, Protein Multimerization, Synapses chemistry
- Abstract
PSD-95 MAGUK family scaffold proteins are multi-domain organisers of synaptic transmission that contain three PDZ domains followed by an SH3-GK domain tandem. This domain architecture allows coordinated assembly of protein complexes composed of neurotransmitter receptors, synaptic adhesion molecules and downstream signalling effectors. Here we show that binding of monomeric CRIPT-derived PDZ
3 ligands to the third PDZ domain of PSD-95 induces functional changes in the intramolecular SH3-GK domain assembly that influence subsequent homotypic and heterotypic complex formation. We identify PSD-95 interactors that differentially bind to the SH3-GK domain tandem depending on its conformational state. Among these interactors, we further establish the heterotrimeric G protein subunit Gnb5 as a PSD-95 complex partner at dendritic spines of rat hippocampal neurons. The PSD-95 GK domain binds to Gnb5, and this interaction is triggered by CRIPT-derived PDZ3 ligands binding to the third PDZ domain of PSD-95, unraveling a hierarchical binding mechanism of PSD-95 complex formation., Competing Interests: NR, BK, SK, MW, CF, SS No competing interests declared, (© 2019, Rademacher et al.)- Published
- 2019
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24. Defective Synapse Maturation and Enhanced Synaptic Plasticity in Shank2 Δex7 -/- Mice.
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Wegener S, Buschler A, Stempel AV, Kang SJ, Lim CS, Kaang BK, Shoichet SA, Manahan-Vaughan D, and Schmitz D
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- Animals, Autism Spectrum Disorder genetics, Disease Models, Animal, Hippocampus physiology, Male, Mice, Inbred C57BL, Mice, Knockout, Nerve Tissue Proteins genetics, Receptors, AMPA physiology, Autism Spectrum Disorder physiopathology, Long-Term Potentiation, Nerve Tissue Proteins physiology, Synapses physiology
- Abstract
Autism spectrum disorders (ASDs) are neurodevelopmental disorders with a strong genetic etiology. Since mutations in human SHANK genes have been found in patients with autism, genetic mouse models are used for a mechanistic understanding of ASDs and the development of therapeutic strategies. SHANKs are scaffold proteins in the postsynaptic density of mammalian excitatory synapses with proposed functions in synaptogenesis, regulation of dendritic spine morphology, and instruction of structural synaptic plasticity. In contrast to all studies so far on the function of SHANK proteins, we have previously observed enhanced synaptic plasticity in Shank2 Δex7
-/- mice. In a series of experiments, we now reproduce these results, further explore the synaptic phenotype, and directly compare our model to the independently generated Shank2 Δex6-7-/- mice. Minimal stimulation experiments reveal that Shank2 Δex7-/- mice possess an excessive fraction of silent (i.e., α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, short, AMPA receptor lacking) synapses. The synaptic maturation deficit emerges during the third postnatal week and constitutes a plausible mechanistic explanation for the mutants' increased capacity for long-term potentiation, both in vivo and in vitro . A direct comparison with Shank2 Δex6-7-/- mice adds weight to the hypothesis that both mouse models show a different set of synaptic phenotypes, possibly due to differences in their genetic background. These findings add to the diversity of synaptic phenotypes in neurodevelopmental disorders and further support the supposed existence of "modifier genes" in the expression and inheritance of ASDs.- Published
- 2018
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