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RISS 인기검색어
- 검색키워드
- 저자 : Jeong Hyeanjeong (검색결과 4 건)
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Pan-HDAC Inhibitors Promote Tau Aggregation by Increasing the Level of Acetylated Tau
Jeong, Hyeanjeong,Shin, Seulgi,Lee, Jun-Seok,Lee, Soo Hyun,Baik, Ja-Hyun,Lim, Sungsu,Kim, Yun Kyung MDPI AG 2019 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.20 No.17
<P>Epigenetic remodeling via histone acetylation has become a popular therapeutic strategy to treat Alzheimer’s disease (AD). In particular, histone deacetylase (HDAC) inhibitors including M344 and SAHA have been elucidated to be new drug candidates for AD, improving cognitive abilities impaired in AD mouse models. Although emerged as a promising target for AD, most of the HDAC inhibitors are poorly selective and could cause unwanted side effects. Here we show that tau is one of the cytosolic substrates of HDAC and the treatment of HDAC inhibitors such as Scriptaid, M344, BML281, and SAHA could increase the level of acetylated tau, resulting in the activation of tau pathology.</P>
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Shin, Seulgi,Lim, Sungsu,Jeong, Hyeanjeong,Kwan, Li Ting,Kim, Yun Kyung MDPI 2018 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.19 No.10
<P>Tau is a neuron-specific microtubule-binding protein that stabilizes microtubules. It is generally thought that highly phosphorylated tau dissociates from microtubules and becomes insoluble aggregates, leading to neuronal degeneration. Due to the implication of tau aggregation in neurodegenerative disorders, including Alzheimer’s disease, great efforts have been made to identify the tau aggregation process. However, tau interaction with tubulin during the aggregation process remains largely unknown. To scrutinize the tau-tubulin interaction, we generated a cell model that enables visualization of the tau-tubulin interaction in a living cell using the Bifluorescence Complementation (BiFC) Technique. Upon diverse chemical stimulation that induced tau pathology, tau-tubulin BiFC cells showed significantly increased levels of BiFC fluorescence, indicating that tau aggregates together with tubulin. Our results suggest that tubulin should be considered as a key component in the tau aggregation process.</P>
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Farag, Ahmed Karam,Hassan, Ahmed H.E.,Jeong, Hyeanjeong,Kwon, Youngji,Choi, Jin Gyu,Oh, Myung Sook,Park, Ki Duk,Kim, Yun Kyung,Roh, Eun Joo Elsevier 2019 European journal of medicinal chemistry Vol.162 No.-
<P><B>Abstract</B></P> <P>Kinase irregularity has been correlated with several complex neurodegenerative tauopathies. Development of selective inhibitors of these kinases might afford promising anti-tauopathy therapies. While DAPK1 inhibitors halt the formation of tau aggregates and counteract neuronal death, CSF1R inhibitors could alleviate the tauopathies-associated neuroinflammation. Herein, we report the design, synthesis, biological evaluation, mechanistic study, and molecular docking study of novel CSF1R/DAPK1 dual inhibitors as multifunctional molecules inhibiting the formation of tau aggregates and neuroinflammation. Compound <B>3l</B>, the most potent DAPK1 inhibitor in the <I>in vitro</I> kinase assay (IC<SUB>50</SUB> = 1.25 μM) was the most effective tau aggregates formation inhibitor in the cellular assay (IC<SUB>50</SUB> = 5.0 μM). Also, compound <B>3l</B> elicited potent inhibition of CSF1R in the <I>in vitro</I> kinase assay (IC<SUB>50</SUB> = 0.15 μM) and promising inhibition of nitric oxide production in LPS-induced BV-2 cells (55% inhibition at 10 μM concentration). Kinase profiling and hERG binding assay anticipated the absence of off-target toxicities while the PAMPA-BBB assay predicted potentially high BBB permeability. The mechanistic study and selectivity profile suggest compound <B>3l</B> as a non-ATP-competitive DAPK1 inhibitor and an ATP-competitive CSF1R inhibitor while the <I>in silico</I> calculations illustrated binding of compound <B>3l</B> to the substrate-binding site of DAPK1. Hence, compound <B>3l</B> might act as a protein-protein interaction inhibitor by hindering DAPK1 kinase reaction through preventing the binding of DAPK1 substrates.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Multifunctional DAPK1 and CSF1R inhibitors for targeting tauopathies. </LI> <LI> <B>3l</B> shows good potency and excellent affinity and within-family selectivity for both kinases. </LI> <LI> Mechanistic study showed <B>3l</B> as non-ATP-competitive DAPK1 inhibitor and ATP-competitive CSF1R inhibitor. </LI> <LI> <B>3l</B> has tau aggregation inhibition and anti-neuroinflammatory activity in cellular assays. </LI> <LI> hERG binding and PAMPA assays revealed <B>3l</B> as a cardiosafe and has a high membrane penetration. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
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Lim Sungsu,Shin Seulgi,Sung Yoonsik,Lee Ha Eun,Kim Kyu Hyeon,Song Ji Yeon,Lee Gwan-Ho,Aziz Hira,Lukianenko Nataliia,Kang Dong Min,Boesen Nicolette,Jeong Hyeanjeong,Abdildinova Aizhan,Lee Junghee,Yu By 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-
Tau oligomers play critical roles in tau pathology and are responsible for neuronal cell death and transmitting the disease in the brain. Accordingly, preventing tau oligomerization has become an important therapeutic strategy to treat tauopathies, including Alzheimer’s disease. However, progress has been slow because detecting tau oligomers in the cellular context is difficult. Working toward tau-targeted drug discovery, our group has developed a tau-BiFC platform to monitor and quantify tau oligomerization. By using the tau-BiFC platform, we screened libraries with FDA-approved and passed phase I drugs and identified levosimendan as a potent anti-tau agent that inhibits tau oligomerization. 14C-isotope labeling of levosimendan revealed that levosimendan covalently bound to tau cysteines, directly inhibiting disulfide-linked tau oligomerization. In addition, levosimendan disassembles tau oligomers into monomers, rescuing neurons from aggregation states. In comparison, the well-known anti-tau agents methylene blue and LMTM failed to protect neurons from tau-mediated toxicity, generating high-molecular-weight tau oligomers. Levosimendan displayed robust potency against tau oligomerization and rescued cognitive declines induced by tauopathy in the TauP301L-BiFC mouse model. Our data present the potential of levosimendan as a disease-modifying drug for tauopathies.
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