Search

Your search keyword '"Dongjoon Im"' showing total 8 results
Start Over Author "Dongjoon Im"
8 results on '"Dongjoon Im"'

1. Genipin and pyrogallol: Two natural small molecules targeting the modulation of disordered proteins in Alzheimer's disease

Author

Sujin Kim, Da Gyeong Hyun, Yunkwon Nam, Soo Jung Shin, Dongjoon Im, Hyeon soo Kim, Seol Hwa Leem, Hyun Ha Park, Byeong-Hyeon Kim, Yong Ho Park, Eunbi Cho, William A. Goddard, III, Dong Hyun Kim, Hugh I. Kim, and Minho Moon

Subjects
Alzheimer’s disease, Amyloid beta, Tau, Genipin, Pyrogallol, Therapeutics. Pharmacology, RM1-950
Abstract

Alzheimer's disease (AD) is characterized by the aggregation of disordered proteins, such as amyloid beta (Aβ) and tau, leading to neurotoxicity and disease progression. Despite numerous efforts, effective inhibitors of Aβ and tau aggregates have not been developed. Thus, we aimed to screen natural small molecules from crude extracts that target various pathologies and are prescribed for patients with neurological diseases. In this study, we screened 162 natural small molecules prescribed for neurological diseases and identified genipin and pyrogallol as hit compounds capable of simultaneously regulating the aggregation of Aβ and tau K18. Moreover, we confirmed the dual modulatory effects of these compounds on the reduction of amyloid-mediated neurotoxicity in vitro and the disassembly of preformed Aβ42 and tau K18 fibrils. Furthermore, we observed the alleviatory effects of genipin and pyrogallol against AD-related pathologies in triple transgenic AD mice. Molecular dynamics and docking simulations revealed the molecular interaction dynamics of genipin and pyrogallol with Aβ42 and tau K18, providing insights into their suppression of aggregation. Our findings suggest the therapeutic potential of genipin and pyrogallol as dual modulators for the treatment of AD by inhibiting aggregation or promoting dissociation of Aβ and tau.

Published
2023
Full Text
View/download PDF

2. Self‐Aggregating Tau Fragments Recapitulate Pathologic Phenotypes and Neurotoxicity of Alzheimer's Disease in Mice

Author

Ly Thi Huong Luu Le, Jeeyoung Lee, Dongjoon Im, Sunha Park, Kyoung‐Doo Hwang, Jung Hoon Lee, Yanxialei Jiang, Yong‐Seok Lee, Young Ho Suh, Hugh I. Kim, and Min Jae Lee

Subjects
aggregation, Alzheimer's disease, axon initial segment, phosphorylation, tau, Science
Abstract

Abstract In tauopathy conditions, such as Alzheimer's disease (AD), highly soluble and natively unfolded tau polymerizes into an insoluble filament; however, the mechanistic details of this process remain unclear. In the brains of AD patients, only a minor segment of tau forms β‐helix‐stacked protofilaments, while its flanking regions form disordered fuzzy coats. Here, it is demonstrated that the tau AD nucleation core (tau‐AC) sufficiently induced self‐aggregation and recruited full‐length tau to filaments. Unexpectedly, phospho‐mimetic forms of tau‐AC (at Ser324 or Ser356) show markedly reduced oligomerization and seeding propensities. Biophysical analysis reveal that the N‐terminus of tau‐AC facilitates the fibrillization kinetics as a nucleation motif, which becomes sterically shielded through phosphorylation‐induced conformational changes in tau‐AC. Tau‐AC oligomers are efficiently internalized into cells via endocytosis and induced endogenous tau aggregation. In primary hippocampal neurons, tau‐AC impaired axon initial segment plasticity upon chronic depolarization and is mislocalized to the somatodendritic compartments. Furthermore, it is observed significantly impaired memory retrieval in mice intrahippocampally injected with tau‐AC fibrils, which corresponds to the neuropathological staining and neuronal loss in the brain. These findings identify tau‐AC species as a key neuropathological driver in AD, suggesting novel strategies for therapeutic intervention.

Published
2023
Full Text
View/download PDF

3. DNA repair and cholesterol-mediated drug efflux induce dose-dependent chemoresistance in nutrient-deprived neuroblastoma cells

Author

Soo Yeon Chae, Dowoon Nam, Do Young Hyeon, Areum Hong, Timothy Dain Lee, Sujin Kim, Dongjoon Im, Jiwon Hong, Chaewon Kang, Ji Won Lee, Daehee Hwang, Sang-Won Lee, and Hugh I. Kim

Subjects
Molecular Biology, Cancer, Proteomics, Science
Abstract

Summary: Neuroblastoma is a solid, heterogeneous pediatric tumor. Chemotherapy is widely used to treat neuroblastoma. However, dose-dependent responses and chemoresistance mechanisms of neuroblastoma cells to anticancer drugs remain challenging. Here, we investigated the dose-dependent effects of topotecan on human neuroblastoma cells (SK-N-SH, SH-SY5Y, and SK-N-BE) under various nutrient supply conditions. Serum-starved human neuroblastoma cells showed reduced toxicity. Their survival rate increased upon treatment with a high concentration (1 μM) of topotecan. Quantitative profiling of global and phosphoproteome identified 12,959 proteins and 48,812 phosphosites, respectively, from SK-N-SH cells. Network analysis revealed that topotecan upregulated DNA repair and cholesterol-mediated topotecan efflux, resulting in topotecan resistance. Results of DNA damage assay, cell cycle, and quantitative analyses of membrane cholesterol supported the validity of these resistance factors and their applicability to all neuroblastoma cells. Our results provide a model for high dose-dependent chemoresistance in neuroblastoma cells that could enable a patient-dependent chemotherapy screening strategy.

Published
2021
Full Text
View/download PDF

5. Kinetic Modulation of Amyloid-β (1-42) Aggregation and Toxicity by Structure-Based Rational Design

Author

Dongjoon Im, Chae Eun Heo, Myung Kook Son, Chae Ri Park, Hugh I. Kim, and Jeong-Mo Choi

Subjects
Amyloid beta-Peptides, Cell Survival, General Chemistry, Molecular Dynamics Simulation, Biochemistry, Catalysis, Peptide Fragments, Kinetics, Colloid and Surface Chemistry, Solubility, X-Ray Diffraction, Cell Line, Tumor, Ion Mobility Spectrometry, Scattering, Small Angle, Mutagenesis, Site-Directed, Humans, Amino Acid Sequence, Protein Multimerization, Dimerization
Abstract

Several point mutations can modulate protein structure and dynamics, leading to different natures. Especially in the case of amyloidogenic proteins closely related to neurodegenerative diseases, structural changes originating from point mutations can affect fibrillation kinetics. Herein, we rationally designed mutant candidates to inhibit the fibrillation process of amyloid-β with its point mutants through multistep

Published
2022

6. ATP Kinetically Modulates Pathogenic Tau Fibrillations

Author

Yun Kyung Kim, Dongjoon Im, Hugh I. Kim, Sungsu Lim, Jong Yoon Han, Chae Eun Heo, Jee Young Lee, and Min Jae Lee

Subjects
Amyloid, Physiology, Cognitive Neuroscience, Lysine, tau Proteins, macromolecular substances, Intrinsically disordered proteins, Fibril, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Adenosine Triphosphate, X-Ray Diffraction, Scattering, Small Angle, medicine, Humans, 030304 developmental biology, Fibrillation, 0303 health sciences, Small-angle X-ray scattering, Cell Biology, General Medicine, Cytosol, chemistry, Biophysics, medicine.symptom, Adenosine triphosphate, 030217 neurology & neurosurgery
Abstract

Advanced understanding of Alzheimer's disease (AD) and several tauopathies over the past decades indicates the pathological importance of tau aggregation in these diseases. Herein, we demonstrated that adenosine triphosphate (ATP), a highly charged anionic molecule found abundantly in the cytosol of cells, catalyzes fibrillation of tau as well as human islet amyloid polypeptide, a representative of basic intrinsically disordered proteins. Our results showed that ATP attracts multiple lysine residues of the four-repeat domain of tau (K18) via supramolecular complexation, thereby forming dimers that are converted to nuclei and accelerate fibril elongation. However, ATP was not directly incorporated into the K18 fibrils, suggesting that ATP plays the role of a catalyst, rather than a reactant, during K18 fibrillation. We also characterized the correlation between ATP dyshomeostasis and tau aggregation in the cellular environment. Our multiple biophysical approaches, including native mass spectrometry (MS), small-angle X-ray scattering (SAXS), and molecular dynamics (MD) simulation, provided insights into the molecular-level influence of ATP on the structural changes and fibrillation of tau.

Published
2020

7. ATP Kinetically Modulates Pathogenic Tau Fibrillations

Author

Jong Yoon Han, Chae Eun Heo, Sungsu Lim, Jeeyoung Lee, Iryna Martsishevska, Dongjoon Im, Min Jae Lee, Yun Kyung Kim, and Hugh I. Kim

Subjects
macromolecular substances
Abstract

Advanced understanding of Alzheimer’s disease (AD) and several tauopathies over the past decades indicates the pathological importance of tau aggregation in these diseases. Herein, we demonstrated that adenosine triphosphate (ATP), a highly charged anionic molecule abundant in the cytosol of cells, catalyses tau fibrillation via supramolecular complexation with basic residues of tau. Our results showed that ATP attracts multiple lysine residues of four-repeat domain of tau (K18), thereby immediately forming dimers which convert to nuclei to accelerate fibril elongation. However, ATP was not directly incorporated in the K18 fibrils suggesting a catalytic role of ATP in K18 fibrillation. We also characterized the correlation between ATP dyshomeostasis and tau aggregation in the cellular environment. Our multiple biophysical approaches, including native mass spectrometry (MS), small-angle X-ray scattering (SAXS), and molecular dynamics (MD) simulation, provided insights into the molecular-level influence of ATP on the structural change and fibrillation of tau.

Published
2020

8. DNA repair and cholesterol-mediated drug efflux induce dose-dependent chemoresistance in nutrient-deprived neuroblastoma cells

Author

Timothy Dain Lee, Sang Won Lee, Ji Won Lee, Dongjoon Im, Areum Hong, Daehee Hwang, Jiwon Hong, Su Jin Kim, Hugh I. Kim, Dowoon Nam, Soo Yeon Chae, Chaewon Kang, and Do Young Hyeon

Subjects
Proteomics, 0301 basic medicine, endocrine system diseases, DNA damage, DNA repair, Science, medicine.medical_treatment, 02 engineering and technology, Article, 03 medical and health sciences, Downregulation and upregulation, Neuroblastoma, medicine, Molecular Biology, Cancer, Chemotherapy, Multidisciplinary, Chemistry, Cell cycle, 021001 nanoscience & nanotechnology, medicine.disease, 030104 developmental biology, Cancer research, Topotecan, Efflux, 0210 nano-technology, medicine.drug
Abstract

Summary Neuroblastoma is a solid, heterogeneous pediatric tumor. Chemotherapy is widely used to treat neuroblastoma. However, dose-dependent responses and chemoresistance mechanisms of neuroblastoma cells to anticancer drugs remain challenging. Here, we investigated the dose-dependent effects of topotecan on human neuroblastoma cells (SK-N-SH, SH-SY5Y, and SK-N-BE) under various nutrient supply conditions. Serum-starved human neuroblastoma cells showed reduced toxicity. Their survival rate increased upon treatment with a high concentration (1 μM) of topotecan. Quantitative profiling of global and phosphoproteome identified 12,959 proteins and 48,812 phosphosites, respectively, from SK-N-SH cells. Network analysis revealed that topotecan upregulated DNA repair and cholesterol-mediated topotecan efflux, resulting in topotecan resistance. Results of DNA damage assay, cell cycle, and quantitative analyses of membrane cholesterol supported the validity of these resistance factors and their applicability to all neuroblastoma cells. Our results provide a model for high dose-dependent chemoresistance in neuroblastoma cells that could enable a patient-dependent chemotherapy screening strategy., Graphical abstract, Highlights The survival rate was increased on nutrient-deprived human neuroblastoma cells Performed proteomics and network analysis-based pharmacodynamic study DNA repair was accelerated resistance in nutrient-deprived human neuroblastoma cells Cholesterol-mediated efflux was increased at resistance conditions, Molecular Biology ; Cancer ; Proteomics

Published
2021

Catalog

Books, media, physical & digital resources
See catalog results