https://scholar.dgist.ac.kr/handle/20.500.11750/313 2026-11-05T06:41:23Z 2026-11-05T06:41:23Z Jeon, Juyeong Yu, Jichang Lee, Sung Bae Seo, Jinsoo https://scholar.dgist.ac.kr/handle/20.500.11750/61059 2026-11-02T08:10:12Z 2026-08-31T15:00:00Z

Title: Alzheimer’s disease through the lens of mesenchymal drift: the collapse of cellular identity Author(s): Jeon, Juyeong; Yu, Jichang; Lee, Sung Bae; Seo, Jinsoo Abstract: Cellular identity is maintained by precise epigenetic regulation, but chronic stress and aging can disrupt this control, leading to mesenchymal drift (MD). Unlike the coordinated process of epithelial-mesenchymal transition (EMT), MD is a stochastic, lineage-independent phenomenon marked by increased epigenetic noise and the widespread activation of profibrotic gene programs. As originally defined, MD requires two components to co-occur: a compromised original cellular identity together with the acquisition or intensification of mesenchymal traits. Applying the MD framework to Alzheimer's disease (AD) provides a new perspective on its pathogenesis. In AD, brain cells do not merely survive or die due to protein toxicity; instead, they lose their specialized identities in an uncoordinated fashion. This transcriptomic drift has been reported across major cell types in the central nervous system: neural progenitor cells differentiate prematurely, mature neurons undergo transcriptomic dedifferentiation, endothelial cells develop features of vascular fibrosis, and glial cells lose their homeostatic functions. Direct enrichment of the MD signature in the AD brain, however, has so far been demonstrated only in astrocytes, oligodendrocytes, and pericytes, and, in our own reanalysis, in human-induced pluripotent stem cell (hiPSC)-derived neural progenitor cells carrying an APP mutation; we distinguish this evidence from observations documenting identity loss or a reactive state alone. We further caution that the novel cell populations identified in recent single-cell transcriptomic studies should not be assumed to represent genuinely new cell types: such clusters may equally reflect a blurring of existing cell lineages, or technical artifacts that produce the same appearance. A drifting transcriptomic profile also does not always signify a corresponding physiological change. These possibilities warrant careful attention, and we therefore emphasize the critical need to integrate transcriptomic data with in vivo functional and morphological validation. This integration is essential to determine whether these identity shifts contribute to AD progression or merely reflect underlying epigenetic instability. [BMB Reports 2026; 59(9): 407-417]

2026-08-31T15:00:00Z 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