Journal Article Epublish 2 citations
PubMed: 39000460 DOI: 10.3390/ijms25137353
Alpha-Synuclein Interaction with UBL3 Is Upregulated by Microsomal Glutathione S-Transferase 3, Leading to Increased Extracellular Transport of the Alpha-Synuclein under Oxidative Stress.
Int J Mol Sci 25(13)
Authors: Jing Yan, Tomoaki Kahyo, Hengsen Zhang, Yashuang Ping, Chi Zhang, Shuyun Jiang, Qianqing Ji, Rafia Ferdous, Md Shoriful Islam, Soho Oyama, Shuhei Aramaki, Tomohito Sato, Mst Afsana Mimi, Md Mahmudul Hasan, Mitsutoshi Setou
Affiliations
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka 431-3192, Japan.
- Quantum Imaging Laboratory, Division of Research and Development in Photonics Technology, Institute of Photonics Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka 431-3192, Japan.
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka 431-3192, Japan. Department of Orthopedic Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka 431-3192, Japan.
- Department of Radiation Oncology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka 431-3192, Japan.
- Translational Biomedical Photonics, Institute of Photonics Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka 431-3192, Japan.
- International Mass Imaging and Spatial Omics Center, Institute of Photonics Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka 431-3192, Japan.
Abstract
Aberrant aggregation of misfolded alpha-synuclein (α-syn), a major pathological hallmark of related neurodegenerative diseases such as Parkinson's disease (PD), can translocate between cells. Ubiquitin-like 3 (UBL3) is a membrane-anchored ubiquitin-fold protein and post-translational modifier. UBL3 promotes protein sorting into small extracellular vesicles (sEVs) and thereby mediates intercellular communication. Our recent studies have shown that α-syn interacts with UBL3 and that this interaction is downregulated after silencing microsomal glutathione S-transferase 3 (MGST3). However, how MGST3 regulates the interaction of α-syn and UBL3 remains unclear. In the present study, we further explored this by overexpressing MGST3. In the split luciferase complementation assay, we found that the interaction between α-syn and UBL3 was upregulated by MGST3. While Western blot and RT-qPCR analyses showed that silencing or overexpression of MGST3 did not significantly alter the expression of α-syn and UBL3, the immunocytochemical staining analysis indicated that MGST3 increased the co-localization of α-syn and UBL3. We suggested roles for the anti-oxidative stress function of MGST3 and found that the effect of MGST3 overexpression on the interaction between α-syn with UBL3 was significantly rescued under excess oxidative stress and promoted intracellular α-syn to extracellular transport. In conclusion, our results demonstrate that MGST3 upregulates the interaction between α-syn with UBL3 and promotes the interaction to translocate intracellular α-syn to the extracellular. Overall, our findings provide new insights and ideas for promoting the modulation of UBL3 as a therapeutic agent for the treatment of synucleinopathy-associated neurodegenerative diseases.
MeSH
Stress, Physiological, Transferases, Neuroprotection, Oxidative Stress, Glutathione Transferase, Synucleinopathies, Alpha-Synuclein, Therapeutics, Synucleins, Neurodegenerative Diseases, Glutathione