Pharmacologic inhibition of PCBP2 biomolecular condensates relieves Alzheimer’s disease

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.

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Publication Details

Journal
Nature Communications
Published
2025-11-26
DOI
https://doi.org/10.1038/s41467-025-65547-9
Citations
1
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
0.81

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article

Pharmacologic inhibition of PCBP2 biomolecular condensates relieves Alzheimer’s disease

Qiuling Pan, Xiaojuan Deng, Shenyou Nie, Yan‐Jiang Wang et al.
1 citations
Nature Communications
RNA Research and Splicing
0.81
article

Pharmacologic inhibition of PCBP2 biomolecular condensates relieves Alzheimer’s disease

Qiuling Pan, Xiaojuan Deng, Shenyou Nie, Yan‐Jiang Wang, Yi He, Xiao‐Xin Yan, Xiao‐Yong Xie, Gui‐Feng Zhou, Yu Xiang, Chen‐Lu Li, Lu Wang, Jiawei Zhang, Guojun Chen, Qi‐Lei Zhang, Ji-Ying Zhou, Xiaojiao Xiang
article en
1 citations

Abstract

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.

Nature CommunicationsVol. 16(1)
Central South University (CN), Army Medical University (CN), Dalian Medical University (CN), Daping Hospital (CN), Second Affiliated Hospital of Chongqing Medical University (CN), The Affiliated Yongchuan Hospital of Chongqing Medical University (CN), Chongqing Medical University (CN)
Hebei University of Science and Technology, National Natural Science Foundation of China, Chongqing Medical University, Hebei University
Openalex Percentile: Top 21%
RNA Research and Splicing
0.81
DOIOpen Access PDFOpenAlex
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