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Mtango N.R.,ICB International | Latham K.E.,Michigan State University | Sutovsky P.,University of Missouri
Advances in Experimental Medicine and Biology | Year: 2014

Post-translational modifications of cellular proteins by ubiquitin and ubiquitin-like protein modifiers are important regulatory events involved in diverse aspects of gamete and embryo physiology including oocyte maturation, fertilization and development of embryos to term. Deubiquitinating enzymes (DUBs) regulate proteolysis by reversing ubiquitination, which targets proteins to the 26S proteasome. The ubiquitin C-terminal hydrolases (UCHs) comprise are DUBs that play a role in the removal of multi-ubiquitin chains. We review here the roles of UCHs in oocytes maturation, fertilization and development in mouse, bovine, porcine and rhesus monkeys. Oocyte UCHs contributes to fertilization and embryogenesis by regulating the physiology of the oocyte and blastomere cortex as well as oocyte spindle. Lack of UCHs in embryos reduces fertilization, while mutant embryos fail to undergo compaction and blastocyst formation. In addition to advancing our understanding of reproductive process, research on the role of deubiquitinating enzymes will allow us to better understand and treat human infertility, and to optimize reproductive performance in agriculturally important livestock species. © 2014 Springer Science+Business Media New York.


Scudder S.L.,University of California at San Diego | Goo M.S.,University of California at San Diego | Cartier A.E.,ICB International | Molteni A.,University of California at San Diego | And 3 more authors.
Journal of Neuroscience | Year: 2014

The trafficking of AMPA receptors (AMPARs) to and from synapses is crucial for synaptic plasticity. Previous work has demonstrated that AMPARs undergo activity-dependent ubiquitination by the E3 ubiquitin ligase Nedd4-1, which promotes their internalization and degradation in lysosomes. Here, we define the molecular mechanisms involved in ubiquitination and deubiquitination of AMPARs. We report that Nedd4-1 is rapidly redistributed to dendritic spines in response to AMPAR activation and not in response to NMDA receptor (NMDAR) activation in cultured rat neurons. In contrast, NMDAR activation directly antagonizes Nedd4-1 function by promoting the deubiquitination of AMPARs. We show that NMDAR activation causes the rapid dephosphorylation and activation of the deubiquitinating enzyme (DUB) USP8. Surface AMPAR levels and synaptic strength are inversely regulated by Nedd4-1 and USP8. Strikingly, we show that homeostatic downscaling of synaptic strength is accompanied by an increase and decrease in Nedd4-1 and USP8 protein levels, respectively. Furthermore, we show that Nedd4-1 is required for homeostatic loss of surface AMPARs and downscaling of synaptic strength. This study provides the first mechanistic evidence for rapid and opposing activity-dependent control of a ubiquitin ligase and DUB at mammalian CNS synapses. We propose that the dynamic regulation of these opposing forces is critical in maintaining synapses and scaling them during homeostatic plasticity. © 2014 the authors.


Patent
ICB International | Date: 2013-01-08

Blood-brain barrier permeable peptide compositions that contain variable antigen binding domains from camelid and/or shark heavy-chain only single-domain antibodies are described. The variable antigen binding domains of the peptide compositions bind to therapeutic and diagnostic biomarkers in the central nervous system, such as the amyloid-beta peptide biomarker for Alzheimers disease. The peptide compositions contain constant domains from human IgG, camelid IgG, and/or shark IgNAR. The peptide compositions include heavy-chain only single-domain antibodies and compositions with one or more variable antigen binding domain bound to one or more constant domains.


Patent
ICB International | Date: 2013-11-20

Blood-brain barrier permeable peptide compositions that contain variable antigen binding domains from camelid and/or shark heavy-chain only single-domain antibodies are described. The variable antigen binding domains of the peptide compositions bind to therapeutic and diagnostic biomarkers in the central nervous system, such as the amyloid-beta peptide biomarker for Alzheimers disease. The peptide compositions contain constant domains from human IgG, camelid IgG, and/or shark IgNAR. The peptide compositions include heavy-chain only single-domain antibodies and compositions with one or more variable antigen binding domain bound to one or more constant domains.


Trademark
ICB International | Date: 2013-12-10

Pharmaceutical preparations for the treatment and diagnosis of neurological diseases, cancer, cardiovascular diseases, allergy, immune and inflammatory diseases, metabolic diseases, and infectious diseases.


Trademark
ICB International | Date: 2011-07-10

Biochemicals, namely, monoclonal antibodies for in vitro scientific or research use.


Trademark
ICB International | Date: 2011-07-10

Biochemicals, namely, monoclonal antibodies for in vitro scientific or research use.


Patent
ICB International | Date: 2013-06-13

Blood-brain barrier permeable peptide compositions that contain variable antigen binding domains from camelid and/or shark heavy-chain only single-domain antibodies are described. The variable antigen binding domains of the peptide compositions bind to therapeutic and diagnostic biomarkers in the central nervous system, such as the amyloid-beta peptide biomarker for Alzheimers disease. The peptide compositions contain constant domains from human IgG, camelid IgG, and/or shark IgNAR. The peptide compositions include heavy-chain only single-domain antibodies and compositions with one or more variable antigen binding domain, bound to one or more constant domains.


Patent
ICB International | Date: 2014-07-16

Blood-brain barrier permeable peptide compositions that contain variable antigen binding domains from camelid and/or shark heavy-chain only single-domain antibodies are described. The variable antigen binding domains of the peptide compositions bind to therapeutic and diagnostic biomarkers in the central nervous system, such as the amyloid-beta peptide biomarker for Alzheimers disease. The peptide compositions contain constant domains from human IgG, camelid IgG, and/or shark IgNAR. The peptide compositions include heavy-chain only single-domain antibodies and compositions with one or more variable antigen binding domain bound to one or more constant domains.


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