Pharmacologic inhibition of PCBP2 biomolecular condensates relieves Alzheimer’s disease

作者：Lu Wang, Xiao‐Yong Xie, Qiuling Pan, Jiawei Zhang, Gui‐Feng Zhou, Qi‐Lei Zhang, Xiao‐Xin Yan, Yu Xiang, Chen‐Lu Li, Yi He, Xiaojiao Xiang, Xiaojuan Deng, Yan‐Jiang Wang, Ji-Ying Zhou, Shenyou Nie, Guojun Chen · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-65547-9 · 被引用次数：3 · 研究领域：RNA Research and Splicing、Alzheimer's disease research and treatments、Neurogenesis and neuroplasticity mechanisms

Biomolecular condensates, membrane-less assemblies formed by phase separation, are implicated in neurodegenerative disease, but their role in Alzheimer's disease (AD) remains unclear. Here, we report that in the brain of AD patients and animal models, an elevation of poly(C)-binding protein 2 (PCBP2) correlates with biomolecular condensation that involves phase separation. These condensates sequester large numbers of mitochondrial and mRNA-binding proteins, leading to the outside impairment of mitochondrial morphology and function, and BACE1 mRNA decay relative to amyloid deposition. We then identify a small molecule CN-0928 that inhibits the condensates by reducing PCBP2 protein level and mitigates AD pathology and cognitive decline, in which CN-0928 binding to a target protein integrator complex subunit 1 (INTS1) allows to regulate PCBP2 expression. Our findings place PCBP2 condensates as a key player that cooperates the seemingly disparate but important pathways, and show pharmacological modulation of PCBP2 as an effective approach for treating AD.