https://scholar.dgist.ac.kr/handle/20.500.11750/313 2026-04-04T17:05:09Z 2026-04-04T17:05:09Z Oh, Jeonghyun Catherine, Christy Kim, Eun Seon Min, Kwang Wook Jeong, Hae Chan Kim, Hyojin Kim, Mijin Ahn, Seung Hae Lukianenko, Nataliia Jo, Min Gu Bak, Hyeon Seok Lim, Sungsu Kim, Yun Kyung Kim, Ho Min Lee, Sung Bae Cho, Hyunju https://scholar.dgist.ac.kr/handle/20.500.11750/57680 2025-07-25T02:42:51Z 2024-12-31T15:00:00Z

Title: Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin Author(s): Oh, Jeonghyun; Catherine, Christy; Kim, Eun Seon; Min, Kwang Wook; Jeong, Hae Chan; Kim, Hyojin; Kim, Mijin; Ahn, Seung Hae; Lukianenko, Nataliia; Jo, Min Gu; Bak, Hyeon Seok; Lim, Sungsu; Kim, Yun Kyung; Kim, Ho Min; Lee, Sung Bae; Cho, Hyunju Abstract: Toxic protein aggregates are associated with various neurodegenerative diseases, including Huntington's disease (HD). Since no current treatment delays the progression of HD, we develop a mechanistic approach to prevent mutant huntingtin (mHttex1) aggregation. Here, we engineer the ATP-independent cytosolic chaperone PEX19, which targets peroxisomal membrane proteins to peroxisomes, to remove mHttex1 aggregates. Using yeast toxicity-based screening with a random mutant library, we identify two yeast PEX19 variants and engineer equivalent mutations into human PEX19 (hsPEX19). These variants effectively delay mHttex1 aggregation in vitro and in cellular HD models. The mutated hydrophobic residue in the alpha 4 helix of hsPEX19 variants binds to the N17 domain of mHttex1, thereby inhibiting the initial aggregation process. Overexpression of the hsPEX19-FV variant rescues HD-associated phenotypes in primary striatal neurons and in Drosophila. Overall, our data reveal that engineering ATP-independent membrane protein chaperones is a promising therapeutic approach for rational targeting of mHttex1 aggregation in HD.

2024-12-31T15:00:00Z Ko, Byung Su Lee, Sung Bae Kim, Tae-Kyung https://scholar.dgist.ac.kr/handle/20.500.11750/57309 2025-07-25T03:23:36Z 2024-10-31T15:00:00Z

Title: A brief guide to analyzing expression quantitative trait loci Author(s): Ko, Byung Su; Lee, Sung Bae; Kim, Tae-Kyung Abstract: Molecular quantitative trait locus (molQTL) mapping has emerged as an important approach for elucidating the functional consequences of genetic variants and unraveling the causal mechanisms underlying diseases or complex traits. However, the variety of analysis tools and sophisticated methodologies available for molQTL studies can be overwhelming for researchers with limited computational expertise. Here, we provide a brief guideline with a curated list of methods and software tools for analyzing expression quantitative trait loci, the most widely studied type of molQTL. © 2024 The Author(s)

2024-10-31T15:00:00Z Dash, Raju Tran, Non-Nuoc Lee, Sung Bae Lee, Byung-Hoon https://scholar.dgist.ac.kr/handle/20.500.11750/56656 2025-07-25T03:27:43Z 2024-05-31T15:00:00Z

Title: Structural Dynamics Analysis of USP14 Activation by AKT-Mediated Phosphorylation Author(s): Dash, Raju; Tran, Non-Nuoc; Lee, Sung Bae; Lee, Byung-Hoon Abstract: Ubiquitin-specific protease 14 (USP14), one of the three major proteasome-associated deubiquitinating enzymes (DUBs), is known to be activated by the AKT-mediated phosphorylation at Ser432. Thereby, AKT can regulate global protein degradation by controlling the ubiquitin-proteasome system (UPS). However, the exact molecular mechanism of USP14 activation by AKT phosphorylation at the atomic level remains unknown. By performing the molecular dynamics (MD) simulation of the USP14 catalytic domain at three different states (inactive, active, and USP14-ubiquitin complex), we characterized the change in structural dynamics by phosphorylation. We observed that the Ser432 phosphorylation induced substantial conformational changes of USP14 in the blocking loop (BL) region to fold it from an open loop into a β-sheet, which is critical for USP14 activation. Furthermore, phosphorylation also increased the frequency of critical hydrogen bonding and salt bridge interactions between USP14 and ubiquitin, which is essential for DUB activity. Structural dynamics insights from this study pinpoint the important local conformational landscape of USP14 by the phosphorylation event, which would be critical for understanding USP14-mediated proteasome regulation and designing future therapeutics. © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

2024-05-31T15:00:00Z Lee, Davin Jeong, Hae Chan Kim, Seung Yeol Chung, Jin Yong Cho, Seok Hwan Kim, Kyoung Ah Cho, Jae Ho Ko, Byung Su Cha, In Jun Chung, Chang Geon Kim, Eun Seon Lee, Sung Bae https://scholar.dgist.ac.kr/handle/20.500.11750/47496 2025-07-25T02:40:26Z 2023-12-31T15:00:00Z

Title: A comparison study of pathological features and drug efficacy between Drosophila models of C9orf72 ALS/FTD Author(s): Lee, Davin; Jeong, Hae Chan; Kim, Seung Yeol; Chung, Jin Yong; Cho, Seok Hwan; Kim, Kyoung Ah; Cho, Jae Ho; Ko, Byung Su; Cha, In Jun; Chung, Chang Geon; Kim, Eun Seon; Lee, Sung Bae Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with a complex genetic basis, presenting both in familial and sporadic forms. The hexanucleotide (G4C2) repeat expansion in the C9orf72 gene, which triggers distinct pathogenic mechanisms, has been identified as a major contributor to familial and sporadic ALS cases. Animal models have proven pivotal in understanding these mechanisms; however, discrepancies between models due to variable transgene sequence, expression levels, and toxicity profiles complicate the translation of findings. Herein, we provide a systematic comparison of seven publicly available Drosophila transgenes modeling the G4C2 expansion under uniform conditions, evaluating variations in their toxicity profiles. Further, we tested three previously characterized disease modifying drugs in selected lines to uncover discrepancies among the tested strains. Our study not only deepens our understanding of the C9orf72 G4C2 mutations but also presents a framework for comparing constructs with minute structural differences. This work may be used to inform experimental designs to better model disease mechanisms and help guide the development of targeted interventions for neurodegenerative diseases, thus bridging the gap between model-based research and therapeutic application. © 2023 The Authors. Published by Elsevier Inc. on behalf of Korean Society for Molecular and Cellular Biology.

2023-12-31T15:00:00Z