112 results on '"Chae-Seok Lim"'
Search Results
2. Autophagy pathway upregulation in a human iPSC-derived neuronal model of Cohen syndrome with VPS13B missense mutations
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You-Kyung Lee, Soo-Kyeong Lee, Suin Choi, Yang Hoon Huh, Ji-Hye Kwak, Yong-Seok Lee, Deok-Jin Jang, Jae-Hyung Lee, Kyungmin Lee, Bong-Kiun Kaang, Chae-Seok Lim, and Jin-A Lee
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Cohen syndrome ,Autophagy ,VPS13B ,iPSC ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Significant clinical symptoms of Cohen syndrome (CS), a rare autosomal recessive disorder, include intellectual disability, facial dysmorphism, postnatal microcephaly, retinal dystrophy, and intermittent neutropenia. CS has been associated with mutations in the VPS13B (vacuolar protein sorting 13 homolog B) gene, which regulates vesicle-mediated protein sorting and transport; however, the cellular mechanism underlying CS pathogenesis in patient-derived neurons remains uncertain. This report states that autophagic vacuoles accumulate in CS fibroblasts and the axonal terminals of CS patient-specific induced pluripotent stem cells (CS iPSC)-derived neurons; additionally, autophagic flux was significantly increased in CS-derived neurons compared to control neurons. VPS13B knockout HeLa cell lines generated using the CRISPR/Cas9 genome editing system showed significant upregulation of autophagic flux, indicating that VSP13B may be associated with autophagy in CS. Transcriptomic analysis focusing on the autophagy pathway revealed that genes associated with autophagosome organization were dysregulated in CS-derived neurons. ATG4C is a mammalian ATG4 paralog and a crucial regulatory component of the autophagosome biogenesis/recycling pathway. ATG4C was significantly upregulated in CS-derived neurons, indicating that autophagy is upregulated in CS neurons. The autophagy pathway in CS neurons may be associated with the pathophysiology exhibited in the neural network of CS patients.
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- 2020
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3. Identification of a novel Shank2 transcriptional variant in Shank2 knockout mouse model of autism spectrum disorder
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Yong-Seok Lee, Nam-Kyung Yu, Jeewan Chun, Jung-eun Yang, Chae-Seok Lim, Hyopil Kim, Gaeun Park, Jin-A Lee, Kyungmin Lee, Bong-Kiun Kaang, and Jae-Hyung Lee
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Autism spectrum disorder ,RNA-seq ,Shank2 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders that are highly heterogeneous in clinical symptoms as well as etiologies. Mutations in SHANK2 are associated with ASD and accordingly, Shank2 knockout mouse shows ASD-like behavioral phenotypes, including social deficits. Intriguingly, two lines of Shank2 knockout (KO) mouse generated by deleting different exons (exon 6–7 or exon 7) showed distinct cellular phenotypes. Previously, we compared gene expressions between Shank2 KOs lacking exon 6–7 (e6–7 KO) and KOs lacking exon 7 (e7 KO) by performing RNA-seq. In this study, we expanded transcriptomic analyses to identify novel transcriptional variants in the KO mice. We found prominent expression of a novel exon (exon 4′ or e4’) between the existing exons 4 and 5 in the Shank2 e6–7 KO model. Expression of the transcriptional variant harboring this novel exon was confirmed by RT-PCR and western blotting. These findings suggest that the novel variant may function as a modifier gene, which contributes to the differences between the two Shank2 mutant lines. Furthermore, our result further represents an example of genetic compensation that may lead to phenotypic heterogeneity among ASD patients with mutations in the same gene.
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- 2020
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4. Rapid Turnover of Cortical NCAM1 Regulates Synaptic Reorganization after Peripheral Nerve Injury
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Hyoung-Gon Ko, Jun-Hyeok Choi, Dong Ik Park, SukJae Joshua Kang, Chae-Seok Lim, Su-Eon Sim, Jaehoon Shim, Ji-Il Kim, Siyong Kim, Tae-Hyeok Choi, Sanghyun Ye, Jaehyun Lee, Pojeong Park, Somi Kim, Jeehaeh Do, Jihye Park, Md Ariful Islam, Hyun Jeong Kim, Christoph W. Turck, Graham L. Collingridge, Min Zhuo, and Bong-Kiun Kaang
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protein turnover ,synaptic reorganization ,neural cell adhesion molecule 1 ,NCAM1 ,neuropathic pain ,Biology (General) ,QH301-705.5 - Abstract
Peripheral nerve injury can induce pathological conditions that lead to persistent sensitized nociception. Although there is evidence that plastic changes in the cortex contribute to this process, the underlying molecular mechanisms are unclear. Here, we find that activation of the anterior cingulate cortex (ACC) induced by peripheral nerve injury increases the turnover of specific synaptic proteins in a persistent manner. We demonstrate that neural cell adhesion molecule 1 (NCAM1) is one of the molecules involved and show that it mediates spine reorganization and contributes to the behavioral sensitization. We show striking parallels in the underlying mechanism with the maintenance of NMDA-receptor- and protein-synthesis-dependent long-term potentiation (LTP) in the ACC. Our results, therefore, demonstrate a synaptic mechanism for cortical reorganization and suggest potential avenues for neuropathic pain treatment.
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- 2018
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5. Understanding the Modulatory Effects of Cannabidiol on Alzheimer’s Disease
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Yinyi Xiong and Chae-Seok Lim
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Alzheimer’s disease ,cannabidiol ,cannabinoid receptor ,endocannabinoid system ,amyloid β ,phosphorylated tau ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Alzheimer’s disease (AD), the most common neurodegenerative disease, is characterized by progressive cognitive impairment. The deposition of amyloid beta (Aβ) and hyperphosphorylated tau is considered the hallmark of AD pathology. Many therapeutic approaches such as Food and Drug Administration-approved cholinesterase inhibitors and N–methyl–D–aspartate receptor antagonists have been used to intervene in AD pathology. However, current therapies only provide limited symptomatic relief and are ineffective in preventing AD progression. Cannabidiol (CBD), a phytocannabinoid devoid of psychoactive responses, provides neuroprotective effects through both cannabinoid and noncannabinoid receptors. Recent studies using an AD mouse model have suggested that CBD can reverse cognitive deficits along with Aβ-induced neuroinflammatory, oxidative responses, and neuronal death. Furthermore, CBD can reduce the accumulation of Aβ and hyperphosphorylation of tau, suggesting the possibility of delaying AD progression. Particularly, the noncannabinoid receptor, peroxisome proliferator-activated receptor gamma, has been suggested to be involved in multiple functions of CBD. Therefore, understanding the underlying mechanisms of CBD is necessary for intervening in AD pathology in depth and for the translation of preclinical studies into clinical settings. In this review, we summarize recent studies on the effect of CBD in AD and suggest problems to be overcome for the therapeutic use of CBD.
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- 2021
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6. PKCα-mediated phosphorylation of LSD1 is required for presynaptic plasticity and hippocampal learning and memory
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Chae-Seok Lim, Hye Jin Nam, Jaehyun Lee, Dongha Kim, Ja Eun Choi, SukJae Joshua Kang, Somi Kim, Hyopil Kim, Chuljung Kwak, Kyu-Won Shim, Siyong Kim, Hyoung-Gon Ko, Ro Un Lee, Eun-Hae Jang, Juyoun Yoo, Jaehoon Shim, Md Ariful Islam, Yong-Seok Lee, Jae-Hyung Lee, Sung Hee Baek, and Bong-Kiun Kaang
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Medicine ,Science - Abstract
Abstract Lysine-specific demethylase 1 (LSD1) is a histone demethylase that participates in transcriptional repression or activation. Recent studies reported that LSD1 is involved in learning and memory. Although LSD1 phosphorylation by PKCα was implicated in circadian rhythmicity, the importance of LSD1 phosphorylation in learning and memory is unknown. In this study, we examined the roles of LSD1 in synaptic plasticity and memory using Lsd1 SA/SA knock-in (KI) mice, in which a PKCα phosphorylation site is mutated. Interestingly, short-term and long-term contextual fear memory as well as spatial memory were impaired in Lsd1 KI mice. In addition, short-term synaptic plasticity, such as paired pulse ratio and post-tetanic potentiation was impaired, whereas long-term synaptic plasticity, including long-term potentiation and long-term depression, was normal. Moreover, the frequency of miniature excitatory postsynaptic current was significantly increased, suggesting presynaptic dysfunction in Lsd1 KI mice. Consistent with this, RNA-seq analysis using the hippocampus of Lsd1 KI mice showed significant alterations in the expressions of presynaptic function-related genes. Intriguingly, LSD1n-SA mutant showed diminished binding to histone deacetylase 1 (HDAC1) compared to LSD1n-WT in SH-SY5Y cells. These results suggest that LSD1 is involved in the regulation of presynaptic gene expression and subsequently regulates the hippocampus-dependent memory in phosphorylation-dependent manner.
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- 2017
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7. Cohen Syndrome Patient iPSC-Derived Neurospheres and Forebrain-Like Glutamatergic Neurons Reveal Reduced Proliferation of Neural Progenitor Cells and Altered Expression of Synapse Genes
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You-Kyung Lee, Su-Kyeong Hwang, Soo-Kyung Lee, Jung-eun Yang, Ji-Hye Kwak, Hyunhyo Seo, Hyunjun Ahn, Yong-Seok Lee, Janghwan Kim, Chae-Seok Lim, Bong-Kiun Kaang, Jae-Hyung Lee, Jin-A Lee, and Kyungmin Lee
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Cohen syndrome ,VPS13B ,induced pluripotent stem cells (iPSCs) ,neurosphere ,transcriptomic analysis ,Medicine - Abstract
Cohen syndrome (CS), a rare autosomal recessive disorder, has been associated with genetic mutations in the VPS13B gene, which regulates vesicle-mediated protein sorting and transport. However, the cellular mechanism underlying CS pathogenesis in patient-derived human neurons remains unknown. We identified a novel compound heterozygous mutation, due to homozygous variation of biparental origin and heterozygous variation inherited from the father, in the VPS13B gene in a 20-month-old female patient. To understand the cellular pathogenic mechanisms, we generated induced pluripotent stem cells (iPSCs) from the fibroblasts of the CS patient. The iPSCs were differentiated into forebrain-like functional glutamatergic neurons or neurospheres. Functional annotation from transcriptomic analysis using CS iPSC-derived neurons revealed that synapse-related functions were enriched among the upregulated and downregulated genes in the CS neurons, whereas processes associated with neurodevelopment were enriched in the downregulated genes. The developing CS neurospheres were small in size compared to control neurospheres, likely due to the reduced proliferation of SOX2-positive neural stem cells. Moreover, the number of SV2B-positive puncta and spine-like structures was significantly reduced in the CS neurons, suggesting synaptic dysfunction. Taking these findings together, for the first time, we report a potential cellular pathogenic mechanism which reveals the alteration of neurodevelopment-related genes and the dysregulation of synaptic function in the human induced neurons differentiated from iPSCs and neurospheres of a CS patient.
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- 2020
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8. Endoplasmic Reticulum Stress Increases DUSP5 Expression via PERK-CHOP Pathway, Leading to Hepatocyte Death
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Hye Jin Jo, Jin Won Yang, Ji Hye Park, Eul Sig Choi, Chae-Seok Lim, Seoul Lee, and Chang Yeob Han
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DUSP5 ,ER stress ,PERK ,CHOP ,hepatocyte ,cell death ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Hepatocyte death is critical for the pathogenesis of liver disease progression, which is closely associated with endoplasmic reticulum (ER) stress responses. However, the molecular basis for ER stress-mediated hepatocyte injury remains largely unknown. This study investigated the effect of ER stress on dual-specificity phosphatase 5 (DUSP5) expression and its role in hepatocyte death. Analysis of Gene Expression Omnibus (GEO) database showed that hepatic DUSP5 levels increased in the patients with liver fibrosis, which was verified in mouse models of liver diseases with ER stress. DUSP5 expression was elevated in both fibrotic and acutely injured liver of mice treated with liver toxicants. Treatment of ER stress inducers enhanced DUSP5 expression in hepatocytes, which was validated in vivo condition. The induction of DUSP5 by ER stress was blocked by either treatment with a chemical inhibitor of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway, or knockdown of C/EBP homologous protein (CHOP), whereas it was not affected by the silencing of IRE1 or ATF6. In addition, DUSP5 overexpression decreased extracellular-signal-regulated kinase (ERK) phosphorylation, but increased cleaved caspase-3 levels. Moreover, the reduction of cell viability under ER stress condition was attenuated by DUSP5 knockdown. In conclusion, DUSP5 expression is elevated in hepatocytes by ER stress through the PERK-CHOP pathway, contributing to hepatocyte death possibly through ERK inhibition.
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- 2019
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9. Spatial Learning and Motor Deficits in Vacuolar Protein Sorting-associated Protein 13b (Vps13b) Mutant Mouse
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Min Jung Kim, Jihae Oh, Su Kyeong Hwang, Kyungmin Lee, Jin-A Lee, Chae Seok Lim, Yong Seok Lee, Jae-Hyung Lee, Ro Un Lee, Hyopil Kim, Bong-Kiun Kaang, and Ja Eun Choi
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0301 basic medicine ,Vacuolar protein sorting ,Cohen syndrome ,Mutant ,Morris water navigation task ,Biology ,medicine.disease ,Hypotonia ,VPS13B ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,030104 developmental biology ,0302 clinical medicine ,Autism spectrum disorder ,Intellectual disability ,medicine ,Neurology (clinical) ,medicine.symptom ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Vacuolar protein sorting-associated protein 13B (VPS13B), also known as COH1, is one of the VPS13 family members which is involved in transmembrane transport, Golgi integrity, and neuritogenesis. Mutations in the VPS13B gene are associated with Cohen syndrome and other cognitive disorders such as intellectual disabilities and autism spectrum disorder (ASD). However, the pathophysiology of VPS13B-associated cognitive deficits is unclear, in part, due to the lack of animal models. Here, we generated a Vps13b exon 2 deletion mutant mouse and analyzed the behavioral phenotypes. We found that Vps13b mutant mice showed reduced activity in open field test and significantly shorter latency to fall in the rotarod test, suggesting that the mutants have motor deficits. In addition, we found that Vps13b mutant mice showed deficits in spatial learning in the hidden platform version of the Morris water maze. The Vps13b mutant mice were normal in other behaviors such as anxiety-like behaviors, working memory and social behaviors. Our results suggest that Vps13b mutant mice may recapitulate key clinical symptoms in Cohen syndrome such as intellectual disability and hypotonia. Vps13b mutant mice may serve as a useful model to investigate the pathophysiology of Vps13b-associated disorders.
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- 2019
10. Perseverative stereotypic behavior of Epac2 KO mice in a reward-based decision making task
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Mootaek Roh, Thomas J. McHugh, Ji-Hye Kwak, Kyungmin Lee, Hyunhyo Seo, Pojeong Park, Hyun Jung Lee, Ja Eun Choi, Juhyun Lee, Chae-Seok Lim, and Bong-Kiun Kaang
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0301 basic medicine ,Cellular activity ,Patch-Clamp Techniques ,Dopamine ,Decision Making ,Prefrontal Cortex ,Striatum ,Biology ,03 medical and health sciences ,Neural activity ,Mice ,0302 clinical medicine ,Reward ,Interneurons ,medicine ,Animals ,Patch clamp ,General Neuroscience ,General Medicine ,medicine.disease ,030104 developmental biology ,Autism ,GABAergic ,Orbitofrontal cortex ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Successfully navigating dynamic environments requires balancing the decision to stay at an optimal choice with that to switch to an alternative to acquire new knowledge. However, the genetic factors and cellular activity shaping this “stay or switch” action decision remains largely unidentified. Here we find that mice carrying a deletion of the exchange protein directly activated by cAMP 2 (Epac2) gene, a putative autism locus, exhibit perseverative “stay” behavior in a dynamic foraging task. Anatomical analysis found that the loss of Epac2 resulted in a significant decrease in the density of PV-expressing interneurons in the ventrolateral orbitofrontal cortex (OFC) and dorsal striatum (dSTR). Further, in vitro whole cell patch clamp recordings of PV+ GABAergic interneurons in the dSTR revealed altered neural activity in Epac2 KO mice in response to dopamine. Our findings highlight a potential role of Epac2 in structural changes and neural responses of PV-expressing GABAergic interneurons in the ventrolateral OFC and dSTR during value-based reinforcement learning and link Epac2 function to abnormal decision-making processes and perseverative behaviors seen in autism.
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- 2020
11. Cohen Syndrome Patient iPSC-Derived Neurospheres and Forebrain-Like Glutamatergic Neurons Reveal Reduced Proliferation of Neural Progenitor Cells and Altered Expression of Synapse Genes
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Janghwan Kim, Jung-eun Yang, Hyunhyo Seo, Su-Kyeong Hwang, Hyunjun Ahn, Soo-Kyung Lee, Ji-Hye Kwak, Jin-A Lee, You-Kyung Lee, Chae-Seok Lim, Kyungmin Lee, Bong-Kiun Kaang, Jae-Hyung Lee, and Yong Seok Lee
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lcsh:Medicine ,medicine.disease_cause ,Article ,Synapse ,03 medical and health sciences ,Glutamatergic ,0302 clinical medicine ,neurosphere ,Neurosphere ,VPS13B ,medicine ,Induced pluripotent stem cell ,transcriptomic analysis ,030304 developmental biology ,0303 health sciences ,Mutation ,Cohen syndrome ,business.industry ,lcsh:R ,General Medicine ,Neural stem cell ,Cell biology ,Forebrain ,induced pluripotent stem cells (iPSCs) ,business ,030217 neurology & neurosurgery - Abstract
Cohen syndrome (CS), a rare autosomal recessive disorder, has been associated with genetic mutations in the VPS13B gene, which regulates vesicle-mediated protein sorting and transport. However, the cellular mechanism underlying CS pathogenesis in patient-derived human neurons remains unknown. We identified a novel compound heterozygous mutation, due to homozygous variation of biparental origin and heterozygous variation inherited from the father, in the VPS13B gene in a 20-month-old female patient. To understand the cellular pathogenic mechanisms, we generated induced pluripotent stem cells (iPSCs) from the fibroblasts of the CS patient. The iPSCs were differentiated into forebrain-like functional glutamatergic neurons or neurospheres. Functional annotation from transcriptomic analysis using CS iPSC-derived neurons revealed that synapse-related functions were enriched among the upregulated and downregulated genes in the CS neurons, whereas processes associated with neurodevelopment were enriched in the downregulated genes. The developing CS neurospheres were small in size compared to control neurospheres, likely due to the reduced proliferation of SOX2-positive neural stem cells. Moreover, the number of SV2B-positive puncta and spine-like structures was significantly reduced in the CS neurons, suggesting synaptic dysfunction. Taking these findings together, for the first time, we report a potential cellular pathogenic mechanism which reveals the alteration of neurodevelopment-related genes and the dysregulation of synaptic function in the human induced neurons differentiated from iPSCs and neurospheres of a CS patient.
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- 2020
- Full Text
- View/download PDF
12. Autophagy pathway upregulation in a human iPSC-derived neuronal model of Cohen syndrome with VPS13B missense mutations
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Bong-Kiun Kaang, You Kyung Lee, Yang Hoon Huh, Chae Seok Lim, Kyungmin Lee, Ji Hye Kwak, Jae-Hyung Lee, Jin-A Lee, Yong Seok Lee, Deok-Jin Jang, Suin Choi, and Soo Kyeong Lee
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Autophagosome ,Autophagosome organization ,Developmental Disabilities ,Induced Pluripotent Stem Cells ,Mutation, Missense ,Vesicular Transport Proteins ,Autophagy-Related Proteins ,Vacuole ,Biology ,lcsh:RC346-429 ,Micro Report ,Fingers ,Gene Knockout Techniques ,Cellular and Molecular Neuroscience ,Downregulation and upregulation ,Intellectual Disability ,VPS13B ,Myopia ,Autophagy ,Humans ,Obesity ,Induced pluripotent stem cell ,Molecular Biology ,lcsh:Neurology. Diseases of the nervous system ,Neurons ,Vacuolar protein sorting ,Cohen syndrome ,iPSC ,Retinal Degeneration ,Autophagosomes ,Fibroblasts ,Axons ,Up-Regulation ,Cell biology ,Cysteine Endopeptidases ,Microscopy, Electron ,Vacuoles ,Microcephaly ,Muscle Hypotonia ,Nerve Net ,HeLa Cells - Abstract
Significant clinical symptoms of Cohen syndrome (CS), a rare autosomal recessive disorder, include intellectual disability, facial dysmorphism, postnatal microcephaly, retinal dystrophy, and intermittent neutropenia. CS has been associated with mutations in the VPS13B (vacuolar protein sorting 13 homolog B) gene, which regulates vesicle-mediated protein sorting and transport; however, the cellular mechanism underlying CS pathogenesis in patient-derived neurons remains uncertain. This report states that autophagic vacuoles accumulate in CS fibroblasts and the axonal terminals of CS patient-specific induced pluripotent stem cells (CS iPSC)-derived neurons; additionally, autophagic flux was significantly increased in CS-derived neurons compared to control neurons. VPS13B knockout HeLa cell lines generated using the CRISPR/Cas9 genome editing system showed significant upregulation of autophagic flux, indicating that VSP13B may be associated with autophagy in CS. Transcriptomic analysis focusing on the autophagy pathway revealed that genes associated with autophagosome organization were dysregulated in CS-derived neurons. ATG4C is a mammalian ATG4 paralog and a crucial regulatory component of the autophagosome biogenesis/recycling pathway. ATG4C was significantly upregulated in CS-derived neurons, indicating that autophagy is upregulated in CS neurons. The autophagy pathway in CS neurons may be associated with the pathophysiology exhibited in the neural network of CS patients.
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- 2020
13. Dysfunction of NMDA receptors in neuronal models of an autism spectrum disorder patient with a DSCAM mutation and in Dscam-knockout mice
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Su Kyeong Hwang, Hyunhyo Seo, Ja Eun Choi, Ariful Islam, Pojeong Park, Kyu Won Shim, Jin-A Lee, You Kyung Lee, Kyungmin Lee, Ji Hye Kwak, Jung eun Yang, Jiah Lee, Ro Un Lee, Yinyi Xiong, Min Jung Kim, Chul Hoon Kim, Bong-Kiun Kaang, Chae Seok Lim, Jae-Hyung Lee, and Yong Seok Lee
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0301 basic medicine ,animal structures ,Dendritic spine ,Autism Spectrum Disorder ,Biology ,medicine.disease_cause ,Receptors, N-Methyl-D-Aspartate ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,DSCAM ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,medicine ,Animals ,Humans ,Induced pluripotent stem cell ,Molecular Biology ,Mice, Knockout ,Neurons ,Gene knockdown ,Mutation ,fungi ,Phenotype ,Psychiatry and Mental health ,030104 developmental biology ,Knockout mouse ,Neuroscience ,Cell Adhesion Molecules ,030217 neurology & neurosurgery - Abstract
Heterogeneity in the etiopathology of autism spectrum disorders (ASD) limits the development of generic remedies, requires individualistic and patient-specific research. Recent progress in human-induced pluripotent stem cell (iPSC) technology provides a novel platform for modeling ASDs for studying complex neuronal phenotypes. In this study, we generated telencephalic induced neuronal (iN) cells from iPSCs derived from an ASD patient with a heterozygous point mutation in the DSCAM gene. The mRNA of DSCAM and the density of DSCAM in dendrites were significantly decreased in ASD compared to control iN cells. RNA sequencing analysis revealed that several synaptic function-related genes including NMDA receptor subunits were downregulated in ASD iN cells. Moreover, NMDA receptor (R)-mediated currents were significantly reduced in ASD compared to control iN cells. Normal NMDA-R-mediated current levels were rescued by expressing wild-type DSCAM in ASD iN cells, and reduced currents were observed by truncated DSCAM expression in control iN cells. shRNA-mediated DSCAM knockdown in control iN cells resulted in the downregulation of an NMDA-R subunit, which was rescued by the overexpression of shRNA-resistant DSCAM. Furthermore, DSCAM was co-localized with NMDA-R components in the dendritic spines of iN cells whereas their co-localizations were significantly reduced in ASD iN cells. Levels of phospho-ERK1/2 were significantly lower in ASD iN cells, suggesting a potential mechanism. A neural stem cell-specific Dscam heterozygous knockout mouse model, showing deficits in social interaction and social memory with reduced NMDA-R currents. These data suggest that DSCAM mutation causes pathological symptoms of ASD by dysregulating NMDA-R function.
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- 2020
14. Identification of a novel Shank2 transcriptional variant in Shank2 knockout mouse model of autism spectrum disorder
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Chae Seok Lim, Hyopil Kim, Jae-Hyung Lee, Yong Seok Lee, Nam Kyung Yu, Jin-A Lee, Bong-Kiun Kaang, Jeewan Chun, Gaeun Park, Kyungmin Lee, and Jung eun Yang
- Subjects
0301 basic medicine ,Transcription, Genetic ,Autism Spectrum Disorder ,Mutant ,Short Report ,RNA-Seq ,Nerve Tissue Proteins ,Biology ,lcsh:RC346-429 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Exon ,0302 clinical medicine ,Animals ,RNA, Messenger ,Molecular Biology ,Gene ,lcsh:Neurology. Diseases of the nervous system ,Genetics ,Mice, Knockout ,Genome ,Genetic heterogeneity ,Brain ,Exons ,Phenotype ,SHANK2 ,030104 developmental biology ,Shank2 ,Gene Expression Regulation ,Knockout mouse ,RNA-seq ,030217 neurology & neurosurgery - Abstract
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders that are highly heterogeneous in clinical symptoms as well as etiologies. Mutations in SHANK2 are associated with ASD and accordingly, Shank2 knockout mouse shows ASD-like behavioral phenotypes, including social deficits. Intriguingly, two lines of Shank2 knockout (KO) mouse generated by deleting different exons (exon 6–7 or exon 7) showed distinct cellular phenotypes. Previously, we compared gene expressions between Shank2 KOs lacking exon 6–7 (e6–7 KO) and KOs lacking exon 7 (e7 KO) by performing RNA-seq. In this study, we expanded transcriptomic analyses to identify novel transcriptional variants in the KO mice. We found prominent expression of a novel exon (exon 4′ or e4’) between the existing exons 4 and 5 in the Shank2 e6–7 KO model. Expression of the transcriptional variant harboring this novel exon was confirmed by RT-PCR and western blotting. These findings suggest that the novel variant may function as a modifier gene, which contributes to the differences between the two Shank2 mutant lines. Furthermore, our result further represents an example of genetic compensation that may lead to phenotypic heterogeneity among ASD patients with mutations in the same gene.
- Published
- 2020
15. Additional file 1 of Identification of a novel Shank2 transcriptional variant in Shank2 knockout mouse model of autism spectrum disorder
- Author
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Lee, Yong-Seok, Nam-Kyung Yu, Jeewan Chun, Yang, Jung-Eun, Chae-Seok Lim, Hyopil Kim, Gaeun Park, Lee, Jin-A, Kyungmin Lee, Bong-Kiun Kaang, and Lee, Jae-Hyung
- Abstract
Additional file 1: Figure S1. Western blot analysis of the Shank2 proteins. The antibody used for the analysis was same with the analysis presented in Fig. 1c. The amount of proteins loading was different and the running time was increased. Figure S2. Multiple sequence alignment and phylogenetic analysis of DNA sequences containing exon 4′ from eight vertebrate species. The novel exon 4′ region was highlighted by red boxes.
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- 2020
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16. β-Adrenergic signaling is required for the induction of a labile state during memory reconsolidation
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Eun Hae Jang, Jihae Oh, Jaehyun Lee, Chae-Seok Lim, Chuljung Kwak, Jae-Ick Kim, and Bong-Kiun Kaang
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Male ,0301 basic medicine ,medicine.drug_class ,Propranolol ,Hippocampal formation ,Receptors, N-Methyl-D-Aspartate ,Membrane Potentials ,Tissue Culture Techniques ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Receptors, Adrenergic, beta ,medicine ,Animals ,Memory impairment ,CA1 Region, Hippocampal ,Anisomycin ,Memory Consolidation ,Neurons ,Neurotransmitter Agents ,Chemistry ,Long-term memory ,General Neuroscience ,Fear ,Receptor antagonist ,Cyclic AMP-Dependent Protein Kinases ,Mice, Inbred C57BL ,030104 developmental biology ,Mental Recall ,NMDA receptor ,Memory consolidation ,Neuroscience ,030217 neurology & neurosurgery ,Signal Transduction ,medicine.drug - Abstract
Memory reconsolidation is the process by which previously consolidated memories reenter a labile state through reactivation of the memory trace and are actively consolidated through de novo protein synthesis. Although extensive studies have shown that β-adrenergic signaling plays a critical role in the restabilization of reactivated memory, its role in the destabilization of long-term memory is not well-studied. In this study, we found that membrane excitability increased in hippocampal CA1 neurons immediately after the retrieval of contextual fear memory. Interestingly, this increase in membrane excitability diminished after treatment with propranolol (a β-adrenergic receptor antagonist), an NMDA receptor antagonist, and a PKA inhibitor. In addition, we found that administration of propranolol prior to, but not after, the retrieval of fear memory ameliorated the memory impairment caused by anisomycin, indicating that inhibition of β-adrenergic signaling blocks the destabilization of contextual fear memory. Taken together, these results indicate that β-adrenergic signaling via NMDA receptors and PKA signaling pathway induces a labile state of long-term memory through increased neuronal membrane excitability.
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- 2018
17. Interregional synaptic maps among engram cells underlie memory formation
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Su-Eon Sim, Chae-Seok Lim, Hyoung-Gon Ko, Jihae Oh, Tae Hyun Kim, Sanghyun Ye, Jaehyun Lee, Ji-il Kim, Jun-Hyeok Choi, Dong Il Choi, and Bong-Kiun Kaang
- Subjects
Male ,0301 basic medicine ,Conditioning, Classical ,Green Fluorescent Proteins ,Long-Term Potentiation ,Neuroimaging ,Engram ,Contextual fear ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Memory ,Neuroplasticity ,Memory formation ,Animals ,Humans ,CA1 Region, Hippocampal ,Neurons ,Neuronal Plasticity ,Multidisciplinary ,Functional connectivity ,HEK 293 cells ,Long-term potentiation ,Fear ,CA3 Region, Hippocampal ,Mice, Inbred C57BL ,HEK293 Cells ,030104 developmental biology ,Synapses ,Synaptic plasticity ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Memories are stored in synapses Memory formation is thought to change the strength of synaptic connections between neurons. However, direct measurements between neurons that participate in a learning process are difficult to obtain. Choi et al. developed the “dual-eGRASP” technique to identify synaptic connections between hippocampal CA3 and CA1 pyramidal cells. This method could label two different sets of synapses so that their convergence on the same dendrites would be quantified. After contextual fear conditioning in mice, the number and size of spines were increased on CA1 engram cells receiving input from CA3 engram cells. Science , this issue p. 430
- Published
- 2018
18. Rapid Turnover of Cortical NCAM1 Regulates Synaptic Reorganization after Peripheral Nerve Injury
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Christoph W. Turck, Somi Kim, Hyun Jeong Kim, Ji-il Kim, Jaehoon Shim, Sanghyun Ye, Hyoung-Gon Ko, Siyong Kim, Jeehaeh Do, Ariful Islam, Sukjae Joshua Kang, Jihye Park, Su-Eon Sim, Chae-Seok Lim, Min Zhuo, Jaehyun Lee, Dong Ik Park, Graham L. Collingridge, Jun-Hyeok Choi, Pojeong Park, Tae-Hyeok Choi, and Bong-Kiun Kaang
- Subjects
Male ,0301 basic medicine ,Dendritic spine ,synaptic reorganization ,Gyrus Cinguli ,Synaptic Transmission ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Peripheral Nerve Injuries ,Cortex (anatomy) ,medicine ,Animals ,lcsh:QH301-705.5 ,Anterior cingulate cortex ,NCAM1 ,neuropathic pain ,Chemistry ,protein turnover ,Long-term potentiation ,CD56 Antigen ,030104 developmental biology ,Nociception ,medicine.anatomical_structure ,lcsh:Biology (General) ,neural cell adhesion molecule 1 ,Synapses ,Peripheral nerve injury ,Neural cell adhesion molecule ,Memory consolidation ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Peripheral nerve injury can induce pathological conditions that lead to persistent sensitized nociception. Although there is evidence that plastic changes in the cortex contribute to this process, the underlying molecular mechanisms are unclear. Here, we find that activation of the anterior cingulate cortex (ACC) induced by peripheral nerve injury increases the turnover of specific synaptic proteins in a persistent manner. We demonstrate that neural cell adhesion molecule 1 (NCAM1) is one of the molecules involved and show that it mediates spine reorganization and contributes to the behavioral sensitization. We show striking parallels in the underlying mechanism with the maintenance of NMDA-receptor- and protein-synthesis-dependent long-term potentiation (LTP) in the ACC. Our results, therefore, demonstrate a synaptic mechanism for cortical reorganization and suggest potential avenues for neuropathic pain treatment.
- Published
- 2018
19. Endoplasmic Reticulum Stress Increases DUSP5 Expression via PERK-CHOP Pathway, Leading to Hepatocyte Death
- Author
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Eul Sig Choi, Hye Jin Jo, Chae-Seok Lim, Seoul Lee, Chang Yeob Han, Ji Hye Park, and Jin Won Yang
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,PERK ,Gene Expression ,Apoptosis ,DUSP5 ,Catalysis ,Article ,Inorganic Chemistry ,lcsh:Chemistry ,03 medical and health sciences ,Mice ,eIF-2 Kinase ,0302 clinical medicine ,medicine ,hepatocyte ,Animals ,Humans ,Physical and Theoretical Chemistry ,Protein kinase A ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,Gene knockdown ,Chemistry ,Kinase ,ATF6 ,Endoplasmic reticulum ,Liver Diseases ,Organic Chemistry ,General Medicine ,Endoplasmic Reticulum Stress ,Computer Science Applications ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,cell death ,lcsh:Biology (General) ,lcsh:QD1-999 ,030220 oncology & carcinogenesis ,Hepatocyte ,Unfolded protein response ,Hepatocytes ,Dual-Specificity Phosphatases ,ER stress ,Transcription Factor CHOP ,CHOP ,Signal Transduction - Abstract
Hepatocyte death is critical for the pathogenesis of liver disease progression, which is closely associated with endoplasmic reticulum (ER) stress responses. However, the molecular basis for ER stress-mediated hepatocyte injury remains largely unknown. This study investigated the effect of ER stress on dual-specificity phosphatase 5 (DUSP5) expression and its role in hepatocyte death. Analysis of Gene Expression Omnibus (GEO) database showed that hepatic DUSP5 levels increased in the patients with liver fibrosis, which was verified in mouse models of liver diseases with ER stress. DUSP5 expression was elevated in both fibrotic and acutely injured liver of mice treated with liver toxicants. Treatment of ER stress inducers enhanced DUSP5 expression in hepatocytes, which was validated in vivo condition. The induction of DUSP5 by ER stress was blocked by either treatment with a chemical inhibitor of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway, or knockdown of C/EBP homologous protein (CHOP), whereas it was not affected by the silencing of IRE1 or ATF6. In addition, DUSP5 overexpression decreased extracellular-signal-regulated kinase (ERK) phosphorylation, but increased cleaved caspase-3 levels. Moreover, the reduction of cell viability under ER stress condition was attenuated by DUSP5 knockdown. In conclusion, DUSP5 expression is elevated in hepatocytes by ER stress through the PERK-CHOP pathway, contributing to hepatocyte death possibly through ERK inhibition.
- Published
- 2019
20. Excitatory neuron-specific SHP2-ERK signaling network regulates synaptic plasticity and memory
- Author
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Jiyeon Ha, Pojeong Park, Tae Hyun Kim, Alcino J. Silva, Minkyung Kang, Hyun Hee Ryu, Jung-Woong Kim, Bong-Kiun Kaang, Yong Gyu Kim, Hyopil Kim, Sang Jeong Kim, Jisu Lee, Yong Seok Lee, Ja Eun Choi, Chul-Hong Kim, and Chae Seok Lim
- Subjects
MAPK/ERK pathway ,Cell type ,MAP Kinase Signaling System ,Long-Term Potentiation ,Mice, Transgenic ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Biology ,Inhibitory postsynaptic potential ,Biochemistry ,Hippocampus ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Memory ,Animals ,Extracellular Signal-Regulated MAP Kinases ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Long-term potentiation ,Cell Biology ,Cell biology ,Ras Signaling Pathway ,Synaptic plasticity ,Mutation ,Excitatory postsynaptic potential ,Ectopic expression ,030217 neurology & neurosurgery - Abstract
Mutations in RAS signaling pathway components cause diverse neurodevelopmental disorders, collectively called RASopathies. Previous studies have suggested that dysregulation in RAS–extracellular signal–regulated kinase (ERK) activation is restricted to distinct cell types in different RASopathies. Some cases of Noonan syndrome (NS) are associated with gain-of-function mutations in the phosphatase SHP2 (encoded by PTPN11); however, SHP2 is abundant in multiple cell types, so it is unclear which cell type(s) contribute to NS phenotypes. Here, we found that expressing the NS-associated mutant SHP2(D61G) in excitatory, but not inhibitory, hippocampal neurons increased ERK signaling and impaired both long-term potentiation (LTP) and spatial memory in mice, although endogenous SHP2 was expressed in both neuronal types. Transcriptomic analyses revealed that the genes encoding SHP2-interacting proteins that are critical for ERK activation, such as GAB1 and GRB2, were enriched in excitatory neurons. Accordingly, expressing a dominant-negative mutant of GAB1, which reduced its interaction with SHP2(D61G), selectively in excitatory neurons, reversed SHP2(D61G)-mediated deficits. Moreover, ectopic expression of GAB1 and GRB2 together with SHP2(D61G) in inhibitory neurons resulted in ERK activation. These results demonstrate that RAS-ERK signaling networks are notably different between excitatory and inhibitory neurons, accounting for the cell type–specific pathophysiology of NS and perhaps other RASopathies.
- Published
- 2019
21. Assessments of cognitive abilities in a mouse model of Parkinson’s disease with a touch screen test
- Author
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Chae-Seok Lim, Bong-Kiun Kaang, and Chuljung Kwak
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Parkinson's disease ,Visual perception ,Reversal Learning ,Disease ,Motor Activity ,Neuropsychological Tests ,Audiology ,Screen test ,Rotarod performance test ,03 medical and health sciences ,Behavioral Neuroscience ,Cognition ,Discrimination, Psychological ,0302 clinical medicine ,Parkinsonian Disorders ,medicine ,Animals ,Oxidopamine ,Computers ,Dopaminergic ,medicine.disease ,Cognitive test ,Mice, Inbred C57BL ,030104 developmental biology ,Rotarod Performance Test ,Exploratory Behavior ,Visual Perception ,Conditioning, Operant ,Cognition Disorders ,Psychology ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Patients with Parkinson's disease (PD) experience both motor output deficits and cognitive disabilities. Various PD rodent models have been developed to investigate the genetic and brain circuit-related causes of PD and have contributed to the basic and clinical research and to therapeutic strategies for this disease. Most studies using PD rodent models have focused on the motor output deficits, rather than cognitive disabilities due to the lack of appropriate testing tools that do not require significant motor abilities. In this study, we assessed the cognitive disabilities of PD model mice using a touch screen test that required only little motor ability. We found that the PD model mice, which had motor deficits caused by unilateral striatal dopaminergic degeneration, successfully underwent operant conditioning with a touch screen test. Additionally, we found that the PD model mice demonstrated impaired location discrimination, but intact attention and reversal learning in the cognitive tests. Therefore, the touch screen test is useful for assessing hidden cognitive disabilities in disease model animals with decreased motor function.
- Published
- 2016
22. Early Correction of N-Methyl-D-Aspartate Receptor Function Improves Autistic-like Social Behaviors in Adult Shank2
- Author
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Ye-Eun Yoo, Hyo Sang Kim, Tobias M. Boeckers, Jihye Kim, Eunjoon Kim, Seungmin Ha, Seojung Mo, Woohyun Kim, Doyoun Kim, Yeonseung Chung, Hyun Kim, Bong-Kiun Kaang, Seungjoon Lee, Hwajin Jung, Yonghan Kwon, Hyojin Kang, Ryunhee Kim, Eunee Lee, Hyejung Won, Won Mah, Seung Min Um, Lara J. Duffney, Yong-hui Jiang, Changuk Chung, Jiseok Lee, Chae Seok Lim, Jin Yong Kim, Haidun Yan, Dongwon Lee, and Taesun Yoo
- Subjects
Adult ,0301 basic medicine ,medicine.medical_specialty ,Autism Spectrum Disorder ,Nerve Tissue Proteins ,Receptors, N-Methyl-D-Aspartate ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Memantine ,Internal medicine ,mental disorders ,medicine ,Animals ,Autistic Disorder ,Social Behavior ,Biological Psychiatry ,Mice, Knockout ,Behavior, Animal ,business.industry ,Age Factors ,medicine.disease ,Pathophysiology ,SHANK2 ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,nervous system ,Autism spectrum disorder ,NMDA receptor ,Autism ,Animal studies ,business ,Excitatory Amino Acid Antagonists ,030217 neurology & neurosurgery ,Social behavior ,medicine.drug - Abstract
Background Autism spectrum disorder involves neurodevelopmental dysregulations that lead to visible symptoms at early stages of life. Many autism spectrum disorder–related mechanisms suggested by animal studies are supported by demonstrated improvement in autistic-like phenotypes in adult animals following experimental reversal of dysregulated mechanisms. However, whether such mechanisms also act at earlier stages to cause autistic-like phenotypes is unclear. Methods We used Shank2−/− mice carrying a mutation identified in human autism spectrum disorder (exons 6 and 7 deletion) and combined electrophysiological and behavioral analyses to see whether early pathophysiology at pup stages is different from late pathophysiology at juvenile and adult stages and whether correcting early pathophysiology can normalize late pathophysiology and abnormal behaviors in juvenile and adult mice. Results Early correction of a dysregulated mechanism in young mice prevents manifestation of autistic-like social behaviors in adult mice. Shank2−/− mice, known to display N-methyl-D-aspartate receptor (NMDAR) hypofunction and autistic-like behaviors at postweaning stages after postnatal day 21 (P21), show the opposite synaptic phenotype—NMDAR hyperfunction—at an earlier preweaning stage (∼P14). Moreover, this NMDAR hyperfunction at P14 rapidly shifts to NMDAR hypofunction after weaning (∼P24). Chronic suppression of the early NMDAR hyperfunction by the NMDAR antagonist memantine (P7–P21) prevents NMDAR hypofunction and autistic-like social behaviors from manifesting at later stages (∼P28 and P56). Conclusions Early NMDAR hyperfunction leads to late NMDAR hypofunction and autistic-like social behaviors in Shank2−/− mice, and early correction of NMDAR dysfunction has the long-lasting effect of preventing autistic-like social behaviors from developing at later stages.
- Published
- 2018
23. Transcription-independent expression of PKMζ in the anterior cingulate cortex contributes to chronically maintained neuropathic pain
- Author
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Pojeong Park, Bong-Kiun Kaang, Chae-Seok Lim, Kyungmin Lee, Sanghyun Ye, Hyoung-Gon Ko, Min Zhuo, and Dae-Hee Han
- Subjects
0301 basic medicine ,Male ,Transcription, Genetic ,Analgesic ,Long-Term Potentiation ,Short Report ,Cell-Penetrating Peptides ,Pharmacology ,Gyrus Cinguli ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Lipopeptides ,0302 clinical medicine ,Transcription (biology) ,Inhibitory peptide ,medicine ,Animals ,Peripheral Nerves ,Receptors, AMPA ,Anterior cingulate cortex ,Protein Kinase C ,neuropathic pain ,Protein Kinase M ,Chemistry ,Protein kinase M ζ ,Chronic pain ,medicine.disease ,Mice, Inbred C57BL ,anterior cingulate cortex ,030104 developmental biology ,Anesthesiology and Pain Medicine ,medicine.anatomical_structure ,Neuropathic pain ,Peripheral nerve injury ,Synapses ,Molecular Medicine ,Neuralgia ,Chronic Pain ,030217 neurology & neurosurgery - Abstract
Protein kinase M ζ is well known for its role in maintaining memory and pain. Previously, we revealed that the activation of protein kinase M ζ in the anterior cingulate cortex plays a role in sustaining neuropathic pain. However, the mechanism by which protein kinase M ζ is expressed in the anterior cingulate cortex by peripheral nerve injury, and whether blocking of protein kinase M ζ using its inhibitor, zeta inhibitory peptide, produces analgesic effects in neuropathic pain maintained chronically after injury, have not previously been resolved. In this study, we show that protein kinase M ζ expression in the anterior cingulate cortex is enhanced by peripheral nerve injury in a transcription-independent manner. We also reveal that the inhibition of protein kinase M ζ through zeta inhibitory peptide treatment is enough to reduce mechanical allodynia responses in mice with one-month-old nerve injuries. However, the zeta inhibitory peptide treatment was only effective for a limited time.
- Published
- 2018
24. Adenomatous polyposis coli-stimulated GEF 1 (Asef1) is a negative regulator of excitatory synaptic function
- Author
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Young Seok Park, Jun Young Oh, Bong-Kiun Kaang, Hyong Kyu Kim, Hyungju Park, Yong Seok Lee, Eung-Gook Kim, Ki Seo Yoo, and Chae Seok Lim
- Subjects
0301 basic medicine ,Nervous system ,animal structures ,Dendritic spine ,Patch-Clamp Techniques ,Adenomatous polyposis coli ,Neurotransmission ,Biochemistry ,Hippocampus ,Synaptic Transmission ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Phosphatidylinositol 3-Kinases ,Excitatory synapse ,medicine ,Animals ,Adenosine Triphosphatases ,Neurons ,Neuronal Plasticity ,biology ,Endosomal Sorting Complexes Required for Transport ,Chemistry ,Excitatory Postsynaptic Potentials ,RNA-Binding Proteins ,Dendrites ,Phosphoproteins ,Cell biology ,Rats ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Synapses ,biology.protein ,Excitatory postsynaptic potential ,Guanine nucleotide exchange factor ,Postsynaptic density ,Disks Large Homolog 4 Protein - Abstract
Guanine nucleotide exchange factors (GEFs) play important roles in many cellular processes, including regulation of the structural plasticity of dendritic spines. A GEF protein, adenomatous polyposis coli-stimulated GEF 1 (Asef1, ARHGEF4) is highly expressed in the nervous system. However, the function of Asef1 has not been investigated in neurons. Here, we present evidence showing that Asef1 negatively regulates the synaptic localization of postsynaptic density protein 95 (PSD-95) in the excitatory synapse by inhibiting Staufen-mediated synaptic localization of PSD-95. Accordingly, Asef1 expression impairs synaptic transmission in hippocampal cultured neurons. In addition, neuronal activity facilitates the dissociation of Asef1 from Staufen in a phosphoinositide 3 kinase (PI3K)-dependent manner. Taken together, our data reveal Asef1 functions as a negative regulator of synaptic localization of PSD-95 and synaptic transmission.
- Published
- 2018
25. Defective Synapse Maturation and Enhanced Synaptic Plasticity in Shank2 Δex7-/- Mice
- Author
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Arne Buschler, Sarah A. Shoichet, Chae-Seok Lim, Stephanie Wegener, Denise Manahan-Vaughan, Bong-Kiun Kaang, Sukjae Joshua Kang, A. Vanessa Stempel, and Dietmar Schmitz
- Subjects
Male ,Dendritic spine ,physiopathology [Autism Spectrum Disorder] ,Autism Spectrum Disorder ,Long-Term Potentiation ,Synaptogenesis ,physiology [Hippocampus] ,Shank2 protein, mouse ,autism ,Nerve Tissue Proteins ,AMPA receptor ,Biology ,Hippocampus ,Synapse ,synapse ,Animals ,ddc:610 ,Receptors, AMPA ,PSD ,genetics [Nerve Tissue Proteins] ,Mice, Knockout ,maturation ,General Neuroscience ,3.1 ,Long-term potentiation ,General Medicine ,New Research ,Mice, Inbred C57BL ,Disease Models, Animal ,shank ,Synapses ,Synaptic plasticity ,Disorders of the Nervous System ,genetics [Autism Spectrum Disorder] ,physiology [Nerve Tissue Proteins] ,LTP ,physiology [Synapses] ,Postsynaptic density ,Neuroscience ,Synapse maturation ,physiology [Receptors, AMPA] - Abstract
Visual 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
26. Specific Expression of Aplysia Phosphodiesterase 4 in Bag Cells Revealed by in situ Hybridization Analysis
- Author
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Bong-Kiun Kaang, Hyoung F. Kim, Jae-Hoon Sim, Chae-Seok Lim, and Deok-Jin Jang
- Subjects
Gene isoform ,Neural facilitation ,Phosphodiesterase ,In situ hybridization ,Biology ,phosphodiesterase 4 ,biology.organism_classification ,Ganglion ,Cell biology ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,nervous system ,Aplysia ,bag cell ,medicine ,Cyclic adenosine monophosphate ,Neurology (clinical) ,Neuron ,in situ hybridization ,Neuroscience ,Rapid Communication - Abstract
Phosphodiesterases (PDEs) play a key role in the regulation of cyclic adenosine monophosphate (cAMP), which in turn mediates various cellular functions including learning and memory. We previously cloned and characterized three PDE4 isoforms (ApPDE4) from Aplysia kurodai. Using reverse transcription polymerase chain reaction (RT-PCR), we found that ApPDE4 isoforms are primarily expressed in the central nervous system. However, the detailed distribution of ApPDE4 mRNA in Aplysia individual ganglions was not evident. In this study, to determine the distribution of ApPDE4 mRNAs in Aplysia ganglions, we performed in situ hybridization (ISH) using a probe targeting ApPDE4, including the PDE catalytic domain. Interestingly, we found the strongest ISH-positive signals in the symmetrical bag cell clusters of the abdominal ganglion. The R2, R14, L7, L2 and L11 neurons in the abdominal ganglion, LP1 neuron in pleural ganglion, and metacerebral (MCC) neurons were ISH-positive. Mechanosensory neurons of the sensory cluster were also stained on the ventral aspect of the right and left pleural ganglia. Taken together, we found the detailed distribution of ApPDE4 mRNA in Aplysia ganglion and support their roles in serotonin (5-HT)-induced synaptic facilitation of Aplysia mechanosensory neurons.
- Published
- 2015
27. Cell type-specific gene expression profiling in brain tissue: comparison between TRAP, LCM and RNA-seq
- Author
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Tae Hyun Kim, Chae-Seok Lim, and Bong-Kiun Kaang
- Subjects
Cell type ,Cell ,RNA-Seq ,Laser Capture Microdissection ,Computational biology ,Biology ,Biochemistry ,Chromatography, Affinity ,Transcriptome ,Cell type-specific ,medicine ,Animals ,Humans ,Molecular Biology ,Laser capture microdissection ,Sequence Analysis, RNA ,Gene Expression Profiling ,Contributed Mini Review ,Brain ,General Medicine ,Neuron ,Molecular biology ,Gene expression profiling ,medicine.anatomical_structure ,Organ Specificity ,Function (biology) - Abstract
The brain is an organ that consists of various cell types. As our knowledge of the structure and function of the brain progresses, cell type-specific research is gaining importance. Together with advances in sequencing technology and bioinformatics, cell type-specific transcriptome studies are providing important insights into brain cell function. In this review, we discuss 3 different cell type-specific transcriptome analyses i.e., Laser Capture Microdissection (LCM), Translating Ribosome Affinity Purification (TRAP)/RiboTag, and single cell RNA-Seq, that are widely used in the field of neuroscience. [BMB Reports 2015; 48(7): 388-394]
- Published
- 2015
28. Development of a Touch-Screen-Based Paradigm for Assessing Working Memory in the Mouse
- Author
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Chuljung Kwak, Chae-Seok Lim, and Bong-Kiun Kaang
- Subjects
Flexibility (engineering) ,Data collection ,Computer science ,business.industry ,Working memory ,Sample (statistics) ,mouse cognition ,working memory ,Cellular and Molecular Neuroscience ,Memory task ,delayed match to position ,Human–computer interaction ,Original Article ,Neurology (clinical) ,Artificial intelligence ,business ,touch screen - Abstract
Assessing the working memory of the rodent by using a touch-screen system has several advantages (e.g., allowing highly accurate data collection and flexibility in memory task design). However, there is currently no available testing paradigm utilizing touch-screen systems that can assess working memory in the mouse. In this study, we developed a touch-screen testing paradigm in which mice were trained to choose a location that is matched to a sample location after a time delay. Consistent with previous studies, this study showed that mice could not only learn the rule in the delayed matched to position (DMTP), but also could retain a transitory memory of the sample position during delay. This indicates that a touch-screen system can provide a DMTP testing platform to assess working memory in the mouse.
- Published
- 2015
29. PKCα-mediated phosphorylation of LSD1 is required for presynaptic plasticity and hippocampal learning and memory
- Author
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Ariful Islam, Siyong Kim, Jaehoon Shim, Eun Hae Jang, Ja Eun Choi, Jae-Hyung Lee, Suk Jae Joshua Kang, Somi Kim, Dong Ha Kim, Hyopil Kim, Sung Hee Baek, Jaehyun Lee, Chuljung Kwak, Chae Seok Lim, Kyu Won Shim, Hyoung Gon Ko, Juyoun Yoo, Ro Un Lee, Hye Jin Nam, Bong-Kiun Kaang, and Yong Seok Lee
- Subjects
Male ,0301 basic medicine ,Memory, Long-Term ,Protein Kinase C-alpha ,animal structures ,Science ,Long-Term Potentiation ,Neural facilitation ,Hippocampus ,Histone Deacetylase 1 ,Biology ,Article ,Animals, Genetically Modified ,Mice ,03 medical and health sciences ,Cell Line, Tumor ,Animals ,Humans ,Learning ,Gene Knock-In Techniques ,Phosphorylation ,Long-Term Synaptic Depression ,Histone Demethylases ,Neurons ,Regulation of gene expression ,Multidisciplinary ,Long-term potentiation ,Fear ,Cell biology ,Memory, Short-Term ,030104 developmental biology ,Gene Expression Regulation ,Biochemistry ,Mutation ,Synaptic plasticity ,Mutagenesis, Site-Directed ,Excitatory postsynaptic potential ,Medicine ,Protein Binding ,Signal Transduction - Abstract
Lysine-specific demethylase 1 (LSD1) is a histone demethylase that participates in transcriptional repression or activation. Recent studies reported that LSD1 is involved in learning and memory. Although LSD1 phosphorylation by PKCα was implicated in circadian rhythmicity, the importance of LSD1 phosphorylation in learning and memory is unknown. In this study, we examined the roles of LSD1 in synaptic plasticity and memory using Lsd1SA/SA knock-in (KI) mice, in which a PKCα phosphorylation site is mutated. Interestingly, short-term and long-term contextual fear memory as well as spatial memory were impaired in Lsd1 KI mice. In addition, short-term synaptic plasticity, such as paired pulse ratio and post-tetanic potentiation was impaired, whereas long-term synaptic plasticity, including long-term potentiation and long-term depression, was normal. Moreover, the frequency of miniature excitatory postsynaptic current was significantly increased, suggesting presynaptic dysfunction in Lsd1 KI mice. Consistent with this, RNA-seq analysis using the hippocampus of Lsd1 KI mice showed significant alterations in the expressions of presynaptic function-related genes. Intriguingly, LSD1n-SA mutant showed diminished binding to histone deacetylase 1 (HDAC1) compared to LSD1n-WT in SH-SY5Y cells. These results suggest that LSD1 is involved in the regulation of presynaptic gene expression and subsequently regulates the hippocampus-dependent memory in phosphorylation-dependent manner.
- Published
- 2017
30. Erratum: BRaf signaling principles unveiled by large-scale human mutation analysis with a rapid lentivirus-based gene replacement method
- Author
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Chae-Seok Lim, Xi Kang, Vincent Mirabella, Huaye Zhang, Qian Bu, Yoichi Araki, Elizabeth T. Hoang, Shiqiang Wang, Ying Shen, Sukwoo Choi, Bong-Kiun Kaang, Qiang Chang, Zhiping P. Pang, Richard L. Huganir, and J. Julius Zhu
- Subjects
Genetics ,Developmental Biology ,Research Paper - Abstract
Here, Lim et al. present a fast cost-effective lentivirus-based rapid gene replacement method to interrogate the physiopathology of BRaf and ∼50 disease-linked BRaf mutants, including all CFC-linked mutants. This study establishes the first efficient procedure that permits large-scale functional analysis of human disease-linked mutations essential for precision medicine.
- Published
- 2017
31. Classification of indoor-outdoor location using combined global positioning system (GPS) and temperature data for personal exposure assessment
- Author
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Chae Seok Lim, Kuhn Uk Lee, and Bolam Lee
- Subjects
Geographic information system ,Microenvironment ,Short Communication ,GPS ,010501 environmental sciences ,030501 epidemiology ,GPS signals ,01 natural sciences ,03 medical and health sciences ,Environmental health ,Indoor outdoor ,0105 earth and related environmental sciences ,Exposure assessment ,Remote sensing ,business.industry ,lcsh:Public aspects of medicine ,Public Health, Environmental and Occupational Health ,Temperature ,Time activity ,lcsh:RA1-1270 ,General Medicine ,Environmental exposure ,Environmental Exposure ,Personal exposure ,Gps data ,Global Positioning System ,Geographic Information Systems ,Environmental science ,Seasons ,0305 other medical science ,business ,Environmental Health ,Environmental Monitoring - Abstract
Objectives The objectives of this study was to determine the accuracy of indoor-outdoor classification based on GPS and temperature data in three different seasons. Methods In the present study, a global positioning system (GPS) was used alongside temperature data collected in the field by a technician who visited 53 different indoor locations during summer, autumn and winter. The indoor-outdoor location was determined by GPS data alone, and in combination with temperature data. Results Determination of location by the GPS signal alone, based on the loss of GPS signal and using the used number of satellites (NSAT) signal factor, simple percentage agreements of 73.6 ± 2.9%, 72.9 ± 3.4%, and 72.1 ± 3.1% were obtained for summer, autumn, and winter, respectively. However, when temperature and GPS data were combined, simple percentage agreements were significantly improved (87.9 ± 3.3%, 84.1 ± 2.8%, and 86.3 ± 3.1%, respectively). A temperature criterion for indoor-outdoor determination of ~ Δ 2°C for 2 min could be applied during all three seasons. Conclusion The results showed that combining GPS and temperature data improved the accuracy of indoor-outdoor determination.
- Published
- 2017
32. Sequestration of PRMT1 and Nd1-L mRNA into ALS-linked FUS mutant R521C-positive aggregates contributes to neurite degeneration upon oxidative stress
- Author
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Hyun-Hee Ryu, Chae-Seok Lim, Bong-Kiun Kaang, Yong Seok Lee, Deok-Jin Jang, Yan Li, Jin-A Lee, Tongtong Liu, Yong-Woo Jun, and Mi-Hee Jun
- Subjects
0301 basic medicine ,Protein-Arginine N-Methyltransferases ,Neurite ,RNA Stability ,RNA-binding protein ,Protein aggregation ,medicine.disease_cause ,Article ,03 medical and health sciences ,Protein Aggregates ,Stress granule ,Cytosol ,Protein Domains ,medicine ,Neurites ,Animals ,Humans ,RNA, Messenger ,Messenger RNA ,Mice, Inbred ICR ,Multidisciplinary ,Chemistry ,Neurodegeneration ,Amyotrophic Lateral Sclerosis ,Wild type ,NADH Dehydrogenase ,medicine.disease ,Cell biology ,Repressor Proteins ,Oxidative Stress ,030104 developmental biology ,HEK293 Cells ,Gene Knockdown Techniques ,Mutation ,Nerve Degeneration ,RNA-Binding Protein FUS ,Mutant Proteins ,Oxidative stress ,Protein Binding - Abstract
Mutations in fused in sarcoma (FUS), a DNA/RNA binding protein, are associated with familial amyotrophic lateral sclerosis (ALS). However, little is known about how ALS-causing mutations alter protein-protein and protein-RNA complexes and contribute to neurodegeneration. In this study, we identified protein arginine methyltransferase 1 (PRMT1) as a protein that more avidly associates with ALS-linked FUS-R521C than with FUS-WT (wild type) or FUS-P525L using co-immunoprecipitation and LC-MS analysis. Abnormal association between FUS-R521C and PRMT1 requires RNA, but not methyltransferase activity. PRMT1 was sequestered into cytosolic FUS-R521C-positive stress granule aggregates. Overexpression of PRMT1 rescued neurite degeneration caused by FUS-R521C upon oxidative stress, while loss of PRMT1 further accumulated FUS-positive aggregates and enhanced neurite degeneration. Furthermore, the mRNA of Nd1-L, an actin-stabilizing protein, was sequestered into the FUS-R521C/PRMT1 complex. Nd1-L overexpression rescued neurite shortening caused by FUS-R521C upon oxidative stress, while loss of Nd1-L further exacerbated neurite shortening. Altogether, these data suggest that the abnormal stable complex of FUS-R521C/PRMT1/Nd1-L mRNA could contribute to neurodegeneration upon oxidative stress. Overall, our study provides a novel pathogenic mechanism of the FUS mutation associated with abnormal protein-RNA complexes upon oxidative stress in ALS and provides insight into possible therapeutic targets for this pathology.
- Published
- 2017
33. Piconewton-Scale Analysis of Ras-BRaf Signal Transduction with Single-Molecule Force Spectroscopy
- Author
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Anpei Ye, J. Julius Zhu, Huaye Zhang, Guangfu Wang, Shi-Qiang Wang, Chae-Seok Lim, Zhuan Zhou, Yanghui Sheng, and Cheng Wen
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Proto-Oncogene Proteins B-raf ,Cell signaling ,Optical Tweezers ,Neurophysiology ,AMPA receptor ,Biology ,Neurotransmission ,Bioinformatics ,Article ,Biomaterials ,03 medical and health sciences ,0302 clinical medicine ,Animals ,Humans ,General Materials Science ,Protein kinase A ,Cells, Cultured ,Effector ,Mental Disorders ,Force spectroscopy ,General Chemistry ,Cell biology ,030104 developmental biology ,Mutation ,ras Proteins ,Signal transduction ,Mitogen-Activated Protein Kinases ,030217 neurology & neurosurgery ,Biotechnology ,Signal Transduction - Abstract
Intermolecular interactions dominate the behavior of signal transduction in various physiological and pathological cell processes, yet assessing these interactions remains a challenging task. Here, this study reports a single-molecule force spectroscopic method that enables functional delineation of two interaction sites (≈35 pN and ≈90 pN) between signaling effectors Ras and BRaf in the canonical mitogen-activated protein kinase (MAPK) pathway. This analysis reveals mutations on BRaf at Q257 and A246, two sites frequently linked to cardio-faciocutaneous syndrome, result in ≈10−30 pN alterations in Ras–BRaf intermolecular binding force. The magnitude of changes in Ras–BRaf binding force correlates with the size of alterations in protein affinity and in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-sensitive glutamate receptor (-R)-mediated synaptic transmission in neurons expressing replacement BRaf mutants, and predicts the extent of learning impairments in animals expressing replacement BRaf mutants. These results establish single-molecule force spectroscopy as an effective platform for evaluating the piconewton-level interaction of signaling molecules and predicting the behavior outcome of signal transduction.
- Published
- 2017
34. Intracellular Membrane Association of the Aplysia cAMP Phosphodiesterase Long and Short Forms via Different Targeting Mechanisms
- Author
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Kun Hyung Kim, Yong-Woo Jun, Chae Seok Lim, Byung-Chang Suh, Yongsoo Park, Yong-Seok Lee, Deok-Jin Jang, Jin-A Lee, and Bong-Kiun Kaang
- Subjects
Serotonin ,Biochemistry ,chemistry.chemical_compound ,Neurobiology ,Aplysia ,Organelle ,Animals ,Protein Isoforms ,Amino Acid Sequence ,Phosphatidylinositol ,Molecular Biology ,biology ,Phosphodiesterase ,Intracellular Membranes ,Cell Biology ,Compartmentalization (fire protection) ,biology.organism_classification ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,Cell biology ,Membrane ,chemistry ,3',5'-Cyclic-AMP Phosphodiesterases ,Synapses ,Protein Multimerization ,Signal transduction ,Intracellular ,Signal Transduction - Abstract
Phosphodiesterases (PDEs) play key roles in cAMP compartmentalization, which is required for intracellular signaling processes, through specific subcellular targeting. Previously, we showed that the long and short forms of Aplysia PDE4 (ApPDE4), which are localized to the membranes of distinct subcellular organelles, play key roles in 5-hydroxytryptamine-induced synaptic facilitation in Aplysia sensory and motor synapses. However, the molecular mechanism of the isoform-specific distinct membrane targeting was not clear. In this study, we further investigated the molecular mechanism of the membrane targeting of the ApPDE4 long and short forms. We found that the membrane targeting of the long form was mediated by hydrophobic interactions, mainly via 16 amino acids at the N-terminal region, whereas the short form was targeted solely to the plasma membrane, mainly by nonspecific electrostatic interactions between their N termini and the negatively charged lipids such as the phosphatidylinositol polyphosphates PI4P and PI(4,5)P2, which are embedded in the inner leaflet of the plasma membrane. Moreover, oligomerization of the long or short form by interaction of their respective upstream conserved region domains, UCR1 and UCR2, enhanced their plasma membrane targeting. These results suggest that the long and short forms of ApPDE4 are distinctly targeted to intracellular membranes through their direct association with the membranes via hydrophobic and electrostatic interactions, respectively.
- Published
- 2014
35. BRaf signaling principles unveiled by large-scale human mutation analysis with a rapid lentivirus-based gene replacement method
- Author
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Xi Kang, Sukwoo Choi, Bong-Kiun Kaang, Ying Shen, Zhiping P. Pang, Vincent R. Mirabella, Yoichi Araki, Qiang Chang, Elizabeth T. Hoang, J. Julius Zhu, Richard L. Huganir, Shi-Qiang Wang, Chae Seok Lim, Qian Bu, and Huaye Zhang
- Subjects
0301 basic medicine ,Male ,Proto-Oncogene Proteins B-raf ,MAP Kinase Signaling System ,Mutant ,Synaptic Transmission ,Rats, Sprague-Dawley ,Tissue Culture Techniques ,03 medical and health sciences ,Transduction (genetics) ,0302 clinical medicine ,Neurodevelopmental disorder ,Genetics ,medicine ,Animals ,Humans ,Small GTPase ,Disease ,Gene ,Cells, Cultured ,Neurons ,biology ,Effector ,Lentivirus ,Gene Transfer Techniques ,biology.organism_classification ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,Mutation ,Mutation testing ,Female ,Erratum ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Rapid advances in genetics are linking mutations on genes to diseases at an exponential rate, yet characterizing the gene-mutation-cell-behavior relationships essential for precision medicine remains a daunting task. More than 350 mutations on BRaf are associated with various tumors, and ∼40 mutations are associated with the neurodevelopmental disorder cardio–facio–cutaneous syndrome (CFC). We developed a fast cost-effective lentivirus-based rapid gene replacement method to interrogate the physiopathology of BRaf and ∼50 disease-linked BRaf mutants, including all CFC-linked mutants. Analysis of simultaneous multiple patch-clamp recordings from 6068 pairs of rat neurons with validation in additional mouse and human neurons and multiple learning tests from 1486 rats identified BRaf as the key missing signaling effector in the common synaptic NMDA-R–CaMKII–SynGap–Ras–BRaf–MEK–ERK transduction cascade. Moreover, the analysis creates the original big data unveiling three general features of BRaf signaling. This study establishes the first efficient procedure that permits large-scale functional analysis of human disease-linked mutations essential for precision medicine.
- Published
- 2016
36. ApCPEB4, a non-prion domain containing homolog of ApCPEB, is involved in the initiation of long-term facilitation
- Author
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Jin-Hee Han, Yong-Seok Lee, Kausik Si, Stefan Kassabov, Sun Lim Choi, Seung-Hee Lee, Yeon Su Chae, Igor Antonov, Sue-Hyun Lee, Jin-A Lee, Chae Seok Lim, Yong-Woo Jun, Jaehoon Shim, Ye Hwang Cheong, Deok-Jin Jang, Bong-Kiun Kaang, and Eric R. Kandel
- Subjects
Central Nervous System ,0301 basic medicine ,Serotonin ,CPEB4 ,Prions ,Long-Term Potentiation ,Protein domain ,Neural facilitation ,RNA-binding protein ,Plasma protein binding ,CPEB ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Protein Domains ,Aplysia ,Neurites ,Protein biosynthesis ,Animals ,Humans ,Amino Acid Sequence ,Cloning, Molecular ,Phosphorylation ,Long-term facilitation ,Molecular Biology ,Transcription factor ,Base Sequence ,Sequence Homology, Amino Acid ,biology ,Research ,HEK 293 cells ,RNA-Binding Proteins ,Cyclic AMP-Dependent Protein Kinases ,HEK293 Cells ,030104 developmental biology ,biology.protein ,RNA ,Neuroscience ,Protein Binding ,Signal Transduction - Abstract
Two pharmacologically distinct types of local protein synthesis are required for synapse- specific long-term synaptic facilitation (LTF) in Aplysia: one for initiation and the other for maintenance. ApCPEB, a rapamycin sensitive prion-like molecule regulates a form of local protein synthesis that is specifically required for the maintenance of the LTF. However, the molecular component of the local protein synthesis that is required for the initiation of LTF and that is sensitive to emetine is not known. Here, we identify a homolog of ApCPEB responsible for the initiation of LTF. ApCPEB4 which we have named after its mammalian CPEB4-like homolog lacks a prion-like domain, is responsive to 5-hydroxytryptamine, and is translated (but not transcribed) in an emetine-sensitive, rapamycin-insensitive, and PKA-dependent manner. The ApCPEB4 binds to different target RNAs than does ApCPEB. Knock-down of ApCPEB4 blocked the induction of LTF, whereas overexpression of ApCPEB4 reduces the threshold of the formation of LTF. Thus, our findings suggest that the two different forms of CPEBs play distinct roles in LTF; ApCPEB is required for maintenance of LTF, whereas the ApCPEB4, which lacks a prion-like domain, is required for the initiation of LTF. Electronic supplementary material The online version of this article (doi:10.1186/s13041-016-0271-x) contains supplementary material, which is available to authorized users.
- Published
- 2016
37. Involvement of β-adrenergic signaling in the induction phase of a labile state during memory reconsolidation
- Author
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Jihae Oh, Jae-Hyun Lee, Chae-Seok Lim, and Bong-Kiun Kaang
- Subjects
β adrenergic signaling ,Chemistry ,General Neuroscience ,Memory consolidation ,Induction Phase ,Cell biology - Published
- 2019
38. Peripheral nerve injury induces rapid turnover of cortical NCAM1 and synaptic reorganization
- Author
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Somi Kim, Jaehoon Shim, Jiah Lee, Sukjae Joshua Kang, Hyun Jeong Kim, Jeehaeh Do, Min Zhuo, Graham L. Collingridge, Hyoung-Gon Ko, Chae-Seok Lim, Sanghyun Ye, Dong Ik Park, Bong-Kiun Kaang, Pojeong Park, Ji-il Kim, Ariful Islam, Su-Eon Sim, Jihye Park, Tae-Hyeok Choi, Christoph W. Turck, Jun-Hyeok Choi, Jae-Hyun Lee, and Siyong Kim
- Subjects
business.industry ,General Neuroscience ,Peripheral nerve injury ,Medicine ,business ,Neuroscience - Published
- 2019
39. Strengthened connections between engrams encode specific memories
- Author
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Hoonwon Lee, Jun-Hyeok Choi, Jae-Hyun Lee, Bong-Kiun Kaang, Tae Hyun Kim, Chae-Seok Lim, Jihae Oh, Hyoung-Gon Ko, Sanghyun Ye, Dong Il Choi, Ji-il Kim, and Su-Eon Sim
- Subjects
Computer science ,General Neuroscience ,Engram ,ENCODE ,Neuroscience - Published
- 2019
40. Spatial memory deficits caused by reduced inhibitory synaptic function in Shank2 mutant mice
- Author
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Taesung Park, Stephanie Wegener, Jihae Oh, Nam-Kyung Yu, Eunjoon Kim, Tobias M. Boeckers, Jungsoo Gim, Chae-Seok Lim, June-Hyun Jeong, Bong-Kiun Kaang, Jae-Hyung Lee, Sung Hee Baek, Hyopil Kim, Dietmar Schmitz, Md. Ariful Islam, Tae Hyun Kim, Min Goo Lee, and Hyoung-Gon Ko
- Subjects
Synaptic function ,Chemistry ,General Neuroscience ,Mutant ,Inhibitory postsynaptic potential ,SHANK2 ,Cell biology - Published
- 2019
41. The Brain-Enriched MicroRNA miR-9-3p Regulates Synaptic Plasticity and Memory
- Author
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Daehyun Baek, Myeong Seong Bak, Jun Hyeok Choi, Jong Eun Park, Sukjae Joshua Kang, Nam Kyung Yu, Daekwan Seo, Hyoung Gon Ko, Joohyun Han, Chae Seok Lim, Yong-Seok Lee, Jaehyun Lee, Heejung Chun, Tae Hyun Kim, Deok-Jin Jang, Eun Hae Jang, Bong-Kiun Kaang, Su Eon Sim, and Jae-Ick Kim
- Subjects
0301 basic medicine ,Male ,Receptors, CXCR4 ,Green Fluorescent Proteins ,Nonsynaptic plasticity ,Biology ,Hippocampus ,Discs Large Homolog 1 Protein ,Dystrophin ,03 medical and health sciences ,Mice ,Transduction, Genetic ,Metaplasticity ,Conditioning, Psychological ,Animals ,Humans ,Maze Learning ,Neuronal memory allocation ,Neuronal Plasticity ,General Neuroscience ,Membrane Proteins ,Long-term potentiation ,Recognition, Psychology ,Synapsin ,Articles ,Fear ,Synapsins ,Mice, Inbred C57BL ,MicroRNAs ,030104 developmental biology ,Synaptic fatigue ,HEK293 Cells ,Synaptic plasticity ,Exploratory Behavior ,Memory consolidation ,Neuroscience ,Guanylate Kinases - Abstract
MicroRNAs (miRNAs) are small, noncoding RNAs that posttranscriptionally regulate gene expression in many tissues. Although a number of brain-enriched miRNAs have been identified, only a few specific miRNAs have been revealed as critical regulators of synaptic plasticity, learning, and memory. miR-9-5p/3p are brain-enriched miRNAs known to regulate development and their changes have been implicated in several neurological disorders, yet their role in mature neurons in mice is largely unknown. Here, we report that inhibition of miR-9-3p, but not miR-9-5p, impaired hippocampal long-term potentiation (LTP) without affecting basal synaptic transmission. Moreover, inhibition of miR-9-3p in the hippocampus resulted in learning and memory deficits. Furthermore, miR-9-3p inhibition increased the expression of the LTP-related genes Dmd and SAP97, the expression levels of which are negatively correlated with LTP. These results suggest that miR-9-3p-mediated gene regulation plays important roles in synaptic plasticity and hippocampus-dependent memory. SIGNIFICANCE STATEMENT Despite the abundant expression of the brain-specific microRNA miR-9-5p/3p in both proliferating and postmitotic neurons, most functional studies have focused on their role in neuronal development. Here, we examined the role of miR-9-5p/3p in adult brain and found that miR-9-3p, but not miR-9-5p, has a critical role in hippocampal synaptic plasticity and memory. Moreover, we identified in vivo binding targets of miR-9-3p that are involved in the regulation of long-term potentiation. Our study provides the very first evidence for the critical role of miR-9-3p in synaptic plasticity and memory in the adult mouse.
- Published
- 2016
42. Enhancing inhibitory synaptic function reverses spatial memory deficits in Shank2 mutant mice
- Author
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Chae Seok Lim, Hyun Hee Ryu, Nam Kyung Yu, Tobias M. Boeckers, Hye Jin Nam, Sukjae Joshua Kang, Hyoung Gon Ko, Hyopil Kim, Bong-Kiun Kaang, Eunjoon Kim, Jung eun Yang, Stephanie Wegener, Jae-Hyung Lee, Jungsoo Gim, Tae Hyun Kim, Yong Seok Lee, Dietmar Schmitz, Taesung Park, Sung Hee Baek, Jaehyun Lee, and Min Goo Lee
- Subjects
0301 basic medicine ,Male ,Autism Spectrum Disorder ,Nerve Tissue Proteins ,Biology ,Neurotransmission ,Inhibitory postsynaptic potential ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Mice ,Animals ,GABRA2 ,Maze Learning ,Social Behavior ,CA1 Region, Hippocampal ,Spatial Memory ,Pharmacology ,Mice, Knockout ,Neurons ,GABAA receptor ,Glutamate receptor ,Receptors, GABA-A ,SHANK2 ,Mice, Inbred C57BL ,030104 developmental biology ,Inhibitory Postsynaptic Potentials ,Knockout mouse ,Mutation ,biology.protein ,Neuroscience ,Ionotropic effect - Abstract
Autism spectrum disorders (ASDs) are a group of developmental disorders that cause variable and heterogeneous phenotypes across three behavioral domains such as atypical social behavior, disrupted communications, and highly restricted and repetitive behaviors. In addition to these core symptoms, other neurological abnormalities are associated with ASD, including intellectual disability (ID). However, the molecular etiology underlying these behavioral heterogeneities in ASD is unclear. Mutations in SHANK2 genes are associated with ASD and ID. Interestingly, two lines of Shank2 knockout mice (e6-7 KO and e7 KO) showed shared and distinct phenotypes. Here, we found that the expression levels of Gabra2, as well as of GABA receptor-mediated inhibitory neurotransmission, are reduced in Shank2 e6-7, but not in e7 KO mice compared with their own wild type littermates. Furthermore, treatment of Shank2 e6-7 KO mice with an allosteric modulator for the GABAA receptor reverses spatial memory deficits, indicating that reduced inhibitory neurotransmission may cause memory deficits in Shank2 e6-7 KO mice. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.
- Published
- 2016
43. Dual roles of the N-terminal coiled-coil domain of an Aplysia sec7 protein: homodimer formation and nuclear export
- Author
-
Yong-Woo Jun, Seung-Hee Lee, Jaehoon Shim, Chae-Seok Lim, Bong-Kiun Kaang, Jin-A Lee, and Deok-Jin Jang
- Subjects
0301 basic medicine ,Neurite ,Active Transport, Cell Nucleus ,Biochemistry ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Aplysia ,Animals ,Guanine Nucleotide Exchange Factors ,Humans ,Amino Acid Sequence ,Nuclear export signal ,Cells, Cultured ,Coiled coil ,Neurons ,biology ,Chemistry ,HEK 293 cells ,biology.organism_classification ,Cell biology ,030104 developmental biology ,Membrane ,HEK293 Cells ,Guanine nucleotide exchange factor ,Protein Multimerization ,Intracellular ,Protein Binding - Abstract
Cytohesin family proteins act as guanine nucleotide exchange factors (GEFs) for the ADP-ribosylation factor (ARF) family of small GTP-binding proteins. Aplysia Sec7 (ApSec7), a member of the cytohesin family in Aplysia, plays key roles in neurite outgrowth in Aplysia neurons. Although ApSec7 has a conserved coiled-coil (CC) domain, its role was not clear. In this study, we found that the CC domain of ApSec7 and ARNO/cytohesin-2 are involved in homodimer formation, leading to efficient plasma membrane targeting of ApSec7 and ARNO/cytohesin-2 in HEK293T cells. Therefore, deletion of the CC domain of ApSec7 and ARNO/cytohesin-2 may result in a loss of dimerization and reduce plasma membrane localization. In addition, the CC domains of ApSec7 and ARNO/cytohesin-2 have partially or fully CRM1-dependent nuclear export signals, respectively. Taken together, our results suggest that the CC domain of cytohesin family proteins, including ApSec7 and ARNO/cytohesin-2, has dual roles in intracellular targeting: increased plasma membrane targeting through homodimer formation and nuclear exclusion through either a CRM1-dependent or a CRM1-independent pathway. This article is protected by copyright. All rights reserved.
- Published
- 2016
44. Everolimus improves neuropsychiatric symptoms in a patient with tuberous sclerosis carrying a novel TSC2 mutation
- Author
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Jae-Hyung Lee, Kyungmin Lee, Jin-A Lee, Bong-Kiun Kaang, Jung eun Yang, Su Kyeong Hwang, Yong-Seok Lee, and Chae Seok Lim
- Subjects
Male ,0301 basic medicine ,Oncology ,Autism ,Neuropsychological Tests ,Tuberous sclerosis ,0302 clinical medicine ,Tuberous Sclerosis ,Intellectual disability ,Medicine ,Exome ,Frameshift Mutation ,Everolimus ,Mutation ,High throughputnucleotide sequencing ,Exome sequencing ,TOR Serine-Threonine Kinases ,Magnetic Resonance Imaging ,Pedigree ,Phenotype ,medicine.anatomical_structure ,Female ,Signal Transduction ,medicine.drug ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Immunoblotting ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Seizures ,Internal medicine ,Tuberous Sclerosis Complex 2 Protein ,Humans ,Amino Acid Sequence ,Autistic Disorder ,Molecular Biology ,PI3K/AKT/mTOR pathway ,Behavior ,Base Sequence ,Dose-Response Relationship, Drug ,business.industry ,Tumor Suppressor Proteins ,Research ,Infant, Newborn ,Infant ,Sequence Analysis, DNA ,medicine.disease ,nervous system diseases ,030104 developmental biology ,TSC1 ,TSC2 ,business ,Neuroscience ,Gene Deletion ,High throughput nucleotide sequencing ,030217 neurology & neurosurgery - Abstract
Tuberous sclerosis complex (TSC) is a neurocutaneous disorder characterized by multiple symptoms including neuropsychological deficits such as seizures, intellectual disability, and autism. TSC is inherited in an autosomal dominant pattern and is caused by mutations in either the TSC1 or TSC2 genes, which enhance activation of the mammalian target of rapamycin (mTOR) signaling pathway. Recent studies have suggested that mTOR inhibitors such as rapamycin can reverse TSC-associated deficits in rodent models of TSC. In addition, clinical trials are ongoing to test the efficacy of mTOR inhibitors toward the psychiatric symptoms associated with TSC. Here, we report a case study of a Korean patient with TSC, who exhibited multiple symptoms including frequent seizures, intellectual disability, language delays, and social problems. We performed whole exome sequencing and identified a novel small deletion mutation in TSC2. Expressing the novel deletion mutant in HEK293T cells significantly increased mTOR pathway activation. Furthermore, everolimus treatment showed not only reduction in SEGA size, but dramatically improved behavioral deficits including autism related behaviors in the patient. In summary, we identified a novel small deletion mutation in TSC2 associated with severe TSC in a Korean family that enhances the activation of mTOR signaling in vitro. Everolimus treatment improved behavioral deficits in the patient. Electronic supplementary material The online version of this article (doi:10.1186/s13041-016-0222-6) contains supplementary material, which is available to authorized users.
- Published
- 2016
45. Neuronal mechanisms and circuits underlying repetitive behaviors in mouse models of autism spectrum disorder
- Author
-
Hyopil Kim, Chae-Seok Lim, and Bong-Kiun Kaang
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Repetitive behaviors ,Neurology ,Autism Spectrum Disorder ,Cognitive Neuroscience ,Behavioral therapy ,Review ,ASD mouse models ,Mice ,03 medical and health sciences ,Behavioral Neuroscience ,Broad spectrum ,Cortico-basal ganglia-thalamic circuits ,0302 clinical medicine ,Basal Ganglia Diseases ,mental disorders ,medicine ,Animals ,Humans ,Set (psychology) ,Biological Psychiatry ,Behavior ,Social communication ,General Medicine ,medicine.disease ,Social relation ,Disease Models, Animal ,030104 developmental biology ,Autism spectrum disorder ,Compulsive Behavior ,Psychology ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Autism spectrum disorder (ASD) refers to a broad spectrum of neurodevelopmental disorders characterized by three central behavioral symptoms: impaired social interaction, impaired social communication, and restricted and repetitive behaviors. However, the symptoms are heterogeneous among patients and a number of ASD mouse models have been generated containing mutations that mimic the mutations found in human patients with ASD. Each mouse model was found to display a unique set of repetitive behaviors. In this review, we summarize the repetitive behaviors of the ASD mouse models and variations found in their neural mechanisms including molecular and electrophysiological features. We also propose potential neuronal mechanisms underlying these repetitive behaviors, focusing on the role of the cortico-basal ganglia-thalamic circuits and brain regions associated with both social and repetitive behaviors. Further understanding of molecular and circuitry mechanisms of the repetitive behaviors associated with ASD is necessary to aid the development of effective treatments for these disorders.
- Published
- 2016
46. Additional file 1: Table S1. of Everolimus improves neuropsychiatric symptoms in a patient with tuberous sclerosis carrying a novel TSC2 mutation
- Author
-
Su-Kyeong Hwang, Lee, Jae-Hyung, Yang, Jung-Eun, Chae-Seok Lim, Lee, Jin-A, Lee, Yong-Seok, Kyungmin Lee, and Bong-Kiun Kaang
- Subjects
body regions ,nervous system ,fungi - Abstract
A list of identified variants that were not detected in unaffected members but detected in affected members (PDF 35 kb)
- Published
- 2016
- Full Text
- View/download PDF
47. Additional file 1: of ApCPEB4, a non-prion domain containing homolog of ApCPEB, is involved in the initiation of long-term facilitation
- Author
-
Seung-Hee Lee, Jaehoon Shim, Ye-Hwang Cheong, Sun-Lim Choi, Yong-Woo Jun, Sue-Hyun Lee, Yeon-Su Chae, Han, Jin-Hee, Lee, Yong-Seok, Lee, Jin-A, Chae-Seok Lim, Kausik Si, Kassabov, Stefan, Antonov, Igor, Kandel, Eric, Bong-Kiun Kaang, and Deok-Jin Jang
- Abstract
Figure S1. A representative Western blot (left) and quantification (right) of ApCPEB4 in Aplysia pleural ganglia extracts prepared from animals exposed to 5-HT in vivo for 2Â h. Total extracts were prepared at indicated times and 20Â Îźg of proteins were blotted with anti-ApCPEB4 antibodies (left, top panel). The same extracts were also stained with Coomassie blue as loading controls (left, bottom panel). (PDF 49 kb)
- Published
- 2016
- Full Text
- View/download PDF
48. A transducible nuclear/nucleolar protein, mLLP, regulates neuronal morphogenesis and synaptic transmission
- Author
-
Hyoung F. Kim, Chuljung Kwak, Seo-Hee Ahn, Sun Lim Choi, Juyoun Yoo, Somi Kim, Deok-Jin Jang, Yong-Seok Lee, Soo Young Choi, Dae Won Kim, Jun Hyeok Choi, Chulhun Kang, Nam Kyung Yu, Chae Seok Lim, Jaehoon Shim, Su Eon Sim, and Bong-Kiun Kaang
- Subjects
0301 basic medicine ,CCCTC-Binding Factor ,Cell Membrane Permeability ,Neurogenesis ,Biology ,Hippocampus ,Synaptic Transmission ,Article ,03 medical and health sciences ,Gene expression ,Animals ,Humans ,Nuclear protein ,RNA, Small Interfering ,Cells, Cultured ,Neurons ,Gene knockdown ,Multidisciplinary ,HEK 293 cells ,Nuclear Proteins ,Dendrites ,Cell biology ,Mice, Inbred C57BL ,Repressor Proteins ,030104 developmental biology ,HEK293 Cells ,CTCF ,Signal transduction ,Neural development ,Signal Transduction - Abstract
Cell-permeable proteins are emerging as unconventional regulators of signal transduction and providing a potential for therapeutic applications. However, only a few of them are identified and studied in detail. We identify a novel cell-permeable protein, mouse LLP homolog (mLLP), and uncover its roles in regulating neural development. We found that mLLP is strongly expressed in developing nervous system and that mLLP knockdown or overexpression during maturation of cultured neurons affected the neuronal growth and synaptic transmission. Interestingly, extracellular addition of mLLP protein enhanced dendritic arborization, demonstrating the non-cell-autonomous effect of mLLP. Moreover, mLLP interacts with CCCTC-binding factor (CTCF) as well as transcriptional machineries and modulates gene expression involved in neuronal growth. Together, these results illustrate the characteristics and roles of previously unknown cell-permeable protein mLLP in modulating neural development.
- Published
- 2015
49. Nuclear Translocation of CAM-Associated Protein Activates Transcription for Long-Term Facilitation in Aplysia
- Author
-
Dong-Hyuk Jang, Hyoung-Gon Ko, Jin-Hee Han, Eric R. Kandel, Yongseok Lee, Craig H. Bailey, Hyong-Kyu Kim, Eunjoon Kim, Ye-Hwang Cheang, Hyoung F. Kim, Sue-Hyun Lee, Bong-Kiun Kaang, Jin-A Lee, Maria Concetta Miniaci, Chae-Seok Lim, Hyungju Park, Dusan Bartsch, Seung-Hee Lee, Lee, Sh, Lim, C, Park, H, Lee, Ja, Han, Jh, Kim, H, Cheang, Yh, Lee, Y, Ko, Hg, Jang, Dh, Miniaci, Maria, Bartsch, D, Kim, E, Bailey, Ch, Kandel, Er, and Kaang, Bk
- Subjects
Transcriptional Activation ,Serotonin ,Cell Adhesion Molecules, Neuronal ,Long-Term Potentiation ,Active Transport, Cell Nucleus ,Biology ,Nervous System ,Synaptic Transmission ,MOLNEURO ,General Biochemistry, Genetics and Molecular Biology ,Synapse ,Downregulation and upregulation ,Aplysia ,medicine ,Animals ,Humans ,Neurons, Afferent ,Cyclic AMP Response Element-Binding Protein ,Cells, Cultured ,Cell Nucleus ,ApCAM ,Biochemistry, Genetics and Molecular Biology(all) ,Anatomy ,biology.organism_classification ,Cyclic AMP-Dependent Protein Kinases ,Cell biology ,Enhancer Elements, Genetic ,medicine.anatomical_structure ,Long Term Memory ,Synaptic plasticity ,Retrograde signaling ,biology.protein ,Phosphorylation ,CREB1 ,Nucleus - Abstract
SummaryRepeated pulses of serotonin (5-HT) induce long-term facilitation (LTF) of the synapses between sensory and motor neurons of the gill-withdrawal reflex in Aplysia. To explore how apCAM downregulation at the plasma membrane and CREB-mediated transcription in the nucleus, both of which are required for the formation of LTF, might relate to each other, we cloned an apCAM-associated protein (CAMAP) by yeast two-hybrid screening. We found that 5-HT signaling at the synapse activates PKA which in turn phosphorylates CAMAP to induce the dissociation of CAMAP from apCAM and the subsequent translocation of CAMAP into the nucleus of sensory neurons. In the nucleus, CAMAP acts as a transcriptional coactivator for CREB1 and is essential for the activation of ApC/EBP required for the initiation of LTF. Combined, our data suggest that CAMAP is a retrograde signaling component that translocates from activated synapses to the nucleus during synapse-specific LTF.
- Published
- 2007
50. Impairment of a parabolic bursting rhythm by the ectopic expression of a small conductance Ca2+-activated K+ channel in Aplysia neuron R15
- Author
-
Heun Soh, Chul-Seung Park, Jin-Hee Han, Chae Seok Lim, Bong-Kiun Kaang, Deok Jin Chang, Yong Lee, and Yong-Seok Lee
- Subjects
Central Nervous System ,Periodicity ,Potassium Channels ,Small-Conductance Calcium-Activated Potassium Channels ,Recombinant Fusion Proteins ,Action Potentials ,Gene Expression ,Biology ,SK channel ,Potassium Channels, Calcium-Activated ,Bursting ,Aplysia ,medicine ,Animals ,Repolarization ,Neurons ,General Neuroscience ,Gene Transfer Techniques ,Afterhyperpolarization ,Hyperpolarization (biology) ,Potassium channel ,Ganglia, Invertebrate ,Electrophysiology ,medicine.anatomical_structure ,nervous system ,Biophysics ,Neuron ,Neuroscience - Abstract
The electrical properties of neurons are produced by the coordinated activity of ion channels. K+ channels play a key role in shaping action potentials and in determining neural firing patterns. Small conductance Ca2+-activated K+ (SK(Ca)) channels are involved in modulating the slow component of afterhyperpolarization (AHP). Here we examine whether rat type 2 SK(Ca) (rSK2) channels can affect the shape of the action potential and the neural firing pattern, by overexpressing rat SK2 channels in Aplysia neuron R15. Our results show that rSK2 overexpression decreased the intra-burst frequency and changed the regular bursting activity of neurons to an irregular bursting or beating pattern in R15. Furthermore, the overexpression of rSK2 channels increased AHP and reduced the duration of the action potential. Thus, our results suggest that ectopic SK(Ca) channels play an important role in regulating the firing pattern and the shape of the action potential.
- Published
- 2003
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