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Inhibition of 14-3-3 Proteins Leads to Schizophrenia-Related Behavioral Phenotypes and Synaptic Defects in Mice.
Title
Inhibition of 14-3-3 Proteins Leads to Schizophrenia-Related Behavioral Phenotypes and Synaptic Defects in Mice.
Creator
Foote, Molly, Qiao, Haifa, Graham, Kourtney, Wu, Yuying, Zhou, Yi
Abstract/Description
The 14-3-3 family of proteins is implicated in the regulation of several key neuronal processes. Previous human and animal studies suggested an association between 14-3-3 dysregulation and schizophrenia. We characterized behavioral and functional changes in transgenic mice that express an isoform-independent 14-3-3 inhibitor peptide in the brain. We recently showed that 14-3-3 functional knockout mice (FKO) exhibit impairments in associative learning and memory. We report here that these 14-3...
Show moreThe 14-3-3 family of proteins is implicated in the regulation of several key neuronal processes. Previous human and animal studies suggested an association between 14-3-3 dysregulation and schizophrenia. We characterized behavioral and functional changes in transgenic mice that express an isoform-independent 14-3-3 inhibitor peptide in the brain. We recently showed that 14-3-3 functional knockout mice (FKO) exhibit impairments in associative learning and memory. We report here that these 14-3-3 FKO mice display other behavioral deficits that correspond to the core symptoms of schizophrenia. These behavioral deficits may be attributed to alterations in multiple neurotransmission systems in the 14-3-3 FKO mice. In particular, inhibition of 14-3-3 proteins results in a reduction of dendritic complexity and spine density in forebrain excitatory neurons, which may underlie the altered synaptic connectivity in the prefrontal cortical synapse of the 14-3-3 FKO mice. At the molecular level, this dendritic spine defect may stem from dysregulated actin dynamics secondary to a disruption of the 14-3-3-dependent regulation of phosphorylated cofilin. Collectively, our data provide a link between 14-3-3 dysfunction, synaptic alterations, and schizophrenia-associated behavioral deficits.
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Date Issued
2015-09-15
Identifier
FSU_pmch_25863357, 10.1016/j.biopsych.2015.02.015, PMC4544659, 25863357, 25863357, S0006-3223(15)00125-0
Format
Citation
14-3-3 proteins are required for hippocampal long-term potentiation and associative learning and memory.
Title
14-3-3 proteins are required for hippocampal long-term potentiation and associative learning and memory.
Creator
Qiao, Haifa, Foote, Molly, Graham, Kourtney, Wu, Yuying, Zhou, Yi
Abstract/Description
14-3-3 is a family of regulatory proteins highly expressed in the brain. Previous invertebrate studies have demonstrated the importance of 14-3-3 in the regulation of synaptic functions and learning and memory. However, the in vivo role of 14-3-3 in these processes has not been determined using mammalian animal models. Here, we report the behavioral and electrophysiological characterization of a new animal model of 14-3-3 proteins. These transgenic mice, considered to be a 14-3-3 functional...
Show more14-3-3 is a family of regulatory proteins highly expressed in the brain. Previous invertebrate studies have demonstrated the importance of 14-3-3 in the regulation of synaptic functions and learning and memory. However, the in vivo role of 14-3-3 in these processes has not been determined using mammalian animal models. Here, we report the behavioral and electrophysiological characterization of a new animal model of 14-3-3 proteins. These transgenic mice, considered to be a 14-3-3 functional knock-out, express a known 14-3-3 inhibitor in various brain regions of different founder lines. We identify a founder-specific impairment in hippocampal-dependent learning and memory tasks, as well as a correlated suppression in long-term synaptic plasticity of the hippocampal synapses. Moreover, hippocampal synaptic NMDA receptor levels are selectively reduced in the transgenic founder line that exhibits both behavioral and synaptic plasticity deficits. Collectively, our findings provide evidence that 14-3-3 is a positive regulator of associative learning and memory at both the behavioral and cellular level.
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Date Issued
2014-04-02
Identifier
FSU_pmch_24695700, 10.1523/JNEUROSCI.4393-13.2014, PMC3972712, 24695700, 24695700, 34/14/4801
Format
Citation
14-3-3 and aggresome formation
Title
14-3-3 and aggresome formation: implications in neurodegenerative diseases..
Creator
Jia, Baohui, Wu, Yuying, Zhou, Yi
Abstract/Description
Protein misfolding and aggregation underlie the pathogenesis of many neurodegenerative diseases. In addition to chaperone-mediated refolding and proteasomal degradation, the aggresome-macroautophagy pathway has emerged as another defense mechanism for sequestration and clearance of toxic protein aggregates in cells. Previously, the 14-3-3 proteins were shown to be indispensable for the formation of aggresomes induced by mutant huntingtin proteins. In a recent study, we have determined that 14...
Show moreProtein misfolding and aggregation underlie the pathogenesis of many neurodegenerative diseases. In addition to chaperone-mediated refolding and proteasomal degradation, the aggresome-macroautophagy pathway has emerged as another defense mechanism for sequestration and clearance of toxic protein aggregates in cells. Previously, the 14-3-3 proteins were shown to be indispensable for the formation of aggresomes induced by mutant huntingtin proteins. In a recent study, we have determined that 14-3-3 functions as a molecular adaptor to recruit chaperone-associated misfolded proteins to dynein motors for transport to aggresomes. This molecular complex involves a dimeric binding of 14-3-3 to both the dynein-intermediate chain (DIC) and an Hsp70 co-chaperone Bcl-2-associated athanogene 3 (BAG3). As 14-3-3 has been implicated in various neurodegenerative diseases, our findings may provide mechanistic insights into its role in managing misfolded protein stress during the process of neurodegeneration.
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Date Issued
2014-03-01
Identifier
FSU_pmch_24549097, PMC4189886, 24549097, 24549097, 28123
Format
Citation
14-3-3 protein targets misfolded chaperone-associated proteins to aggresomes.
Title
14-3-3 protein targets misfolded chaperone-associated proteins to aggresomes.
Creator
Xu, Zhe, Graham, Kourtney, Foote, Molly, Liang, Fengshan, Rizkallah, Raed, Hurt, Myra, Wang, Yanchang, Wu, Yuying, Zhou, Yi
Abstract/Description
The aggresome is a key cytoplasmic organelle for sequestration and clearance of toxic protein aggregates. Although loading misfolded proteins cargos to dynein motors has been recognized as an important step in the aggresome formation process, the molecular machinery that mediates the association of cargos with the dynein motor is poorly understood. Here, we report a new aggresome-targeting pathway that involves isoforms of 14-3-3, a family of conserved regulatory proteins. 14-3-3 interacts...
Show moreThe aggresome is a key cytoplasmic organelle for sequestration and clearance of toxic protein aggregates. Although loading misfolded proteins cargos to dynein motors has been recognized as an important step in the aggresome formation process, the molecular machinery that mediates the association of cargos with the dynein motor is poorly understood. Here, we report a new aggresome-targeting pathway that involves isoforms of 14-3-3, a family of conserved regulatory proteins. 14-3-3 interacts with both the dynein-intermediate chain (DIC) and an Hsp70 co-chaperone Bcl-2-associated athanogene 3 (BAG3), thereby recruiting chaperone-associated protein cargos to dynein motors for their transport to aggresomes. This molecular cascade entails functional dimerization of 14-3-3, which we show to be crucial for the formation of aggresomes in both yeast and mammalian cells. These results suggest that 14-3-3 functions as a molecular adaptor to promote aggresomal targeting of misfolded protein aggregates and may link such complexes to inclusion bodies observed in various neurodegenerative diseases.
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Date Issued
2013-09-15
Identifier
FSU_pmch_23843611, 10.1242/jcs.126102, PMC3772389, 23843611, 23843611, jcs.126102
Format
Citation
Intracellular regions of the Eag potassium channel play a critical role in generation of voltage-dependent currents.
Title
Intracellular regions of the Eag potassium channel play a critical role in generation of voltage-dependent currents.
Creator
Li, Yong, Liu, Xinqiu, Wu, Yuying, Xu, Zhe, Li, Hongqin, Griffith, Leslie C, Zhou, Yi
Abstract/Description
Folding, assembly, and trafficking of ion channels are tightly controlled processes and are important for biological functions relevant to health and disease. Here, we report that functional expression of the Eag channel is temperature-sensitive by a mechanism that is independent of trafficking or surface targeting of the channel protein. Eag channels in cells grown at 37 °C exhibit voltage-evoked gating charge movements but fail to conduct K(+) ions. By mutagenesis and chimeric channel...
Show moreFolding, assembly, and trafficking of ion channels are tightly controlled processes and are important for biological functions relevant to health and disease. Here, we report that functional expression of the Eag channel is temperature-sensitive by a mechanism that is independent of trafficking or surface targeting of the channel protein. Eag channels in cells grown at 37 °C exhibit voltage-evoked gating charge movements but fail to conduct K(+) ions. By mutagenesis and chimeric channel studies, we show that the N- and C-terminal regions are involved in controlling a step after movement of the voltage sensor, as well as in regulating biophysical properties of the Eag channel. Synthesis and assembly of Eag at high temperature disrupt the ability of these domains to carry out their function. These results suggest an important role of the intracellular regions in the generation of Eag currents.
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Date Issued
2011-01-14
Identifier
FSU_pmch_21059657, 10.1074/jbc.M110.184077, PMC3020747, 21059657, 21059657, M110.184077
Format
Citation
Intracellular linkers are involved in Mg2+-dependent modulation of the Eag potassium channel.
Title
Intracellular linkers are involved in Mg2+-dependent modulation of the Eag potassium channel.
Creator
Liu, Xinqiu, Wu, Yuying, Zhou, Yi
Abstract/Description
Modulation of activation kinetics by divalent ions is one of the characteristic features of Eag channels. Here, we report that Mg(2+)-dependent deceleration of Eag channel activation is significantly attenuated by a G297E mutation, which exhibits a gain-of-function phenotype in Drosophila by suppressing the effect of shaker mutation on behavior and neuronal excitability. The G297 residue is located in the intracellular linker of transmembrane segments S2 and S3, and is thus not involved in...
Show moreModulation of activation kinetics by divalent ions is one of the characteristic features of Eag channels. Here, we report that Mg(2+)-dependent deceleration of Eag channel activation is significantly attenuated by a G297E mutation, which exhibits a gain-of-function phenotype in Drosophila by suppressing the effect of shaker mutation on behavior and neuronal excitability. The G297 residue is located in the intracellular linker of transmembrane segments S2 and S3, and is thus not involved in direct binding of Mg(2+) ions. Moreover, mutation of the only positively charged residue in the other intracellular linker between S4 and S5 also results in a dramatic reduction of Mg(2+)-dependent modulation of Eag activation kinetics. Collectively, the two mutations in eag eliminate or even paradoxically reverse the effect of Mg(2+) on channel activation and inactivation kinetics. Together, these results suggest an important role of the intracellular linker regions in gating processes of Eag channels.
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Date Issued
2010-07-01
Identifier
FSU_pmch_20855938, 10.4161/chan.4.4.12329, PMC3322480, 20855938, 20855938, 12329
Format
Citation