Pharmacological interventions on GSK3β phosphorylation-mediated tau aggregation by modulating phase separation of tau proline-rich domain

Shan Sun; Siqian Chen; Junqiu He; Bojun Yang; Yingping Zhang; Ningning Li; Hongfeng Wang; Kin Yip Tam; Zheng Ying

doi:10.1016/j.biopha.2025.118290

Pharmacological interventions on GSK3β phosphorylation-mediated tau aggregation by modulating phase separation of tau proline-rich domain

Biomed Pharmacother. 2025 Jun 27:189:118290. doi: 10.1016/j.biopha.2025.118290. Online ahead of print.

Authors

Shan Sun¹, Siqian Chen¹, Junqiu He², Bojun Yang³, Yingping Zhang³, Ningning Li³, Hongfeng Wang⁴, Kin Yip Tam⁵, Zheng Ying⁶

Affiliations

¹ Faculty of Health Sciences, University of Macau, Taipa, Macau, China; Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China.
² Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
³ Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China.
⁴ Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; MOE Key Laboratory of Geriatric Diseases and Immunology, College of Pharmaceutical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: wanghongfeng@suda.edu.cn.
⁵ Faculty of Health Sciences, University of Macau, Taipa, Macau, China. Electronic address: kintam@um.edu.mo.
⁶ Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; MOE Key Laboratory of Geriatric Diseases and Immunology, College of Pharmaceutical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China; Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: zheng.ying@suda.edu.cn.

PMID: 40580878
DOI: 10.1016/j.biopha.2025.118290

Abstract

Tau pathological aggregation in neurofibrillary tangles is a hallmark of several neurodegenerative diseases, including Alzheimer's disease. Phase separation is a thermodynamic process that plays an important role in biomolecular membrane-less condensate formation, while abnormal phase separation of tau leads to pathological aggregate formation. However, the detailed molecular mechanism underlying tau condensation remains not fully understood. Moreover, whether condensation-based pharmacological intervention will be helpful for the treatment of tau-associated neurodegenerative diseases remains elusive. Here, we used an optogenetic tool (optoDroplets) in combination with cell biology and pharmacology to explore the contribution of different domains for tau condensation in cells, and we found that proline-rich domain (PRD) phosphorylation, which is mainly regulated by glycogen synthase kinase 3 β (GSK3β), plays important roles for tau condensation. Moreover, phosphorylation of tau PRD regulates its mis-localization on nuclear speckle. Interestingly and importantly, we found that pharmacological inhibition of GSK3β can impede abnormal tau condensation to slow down the tau-associated pathological process.

Keywords: Alzheimer’s disease; Condensation; GSK3β; Phase separation; Proline-rich domain; Tau.