Dion William, Tao Yuren, Chambers Maci, Zhao Shanshan, Arbuckle Riley K, Sun Michelle, Kubra Syeda, Schaich Matthew A, Nie Yuhang, Ye Megan, Jamal Imran, Larsen Mads B, Camarco Daniel, Ickes Eleanor, Wang Haokun H, DuPont C, Wang Bingjie, Liu Silvia, Pi Shaohua, Van Houten Bennett, Chen Bill B, Chen Yuanyuan, Chen Xu, Zhu Bokai
Aging Institute of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Neuroscience, School of Medicine, University of California, San Diego, CA, USA.
Nat Commun. 2025 Aug 5;16(1):7065. doi: 10.1038/s41467-025-62242-7.
Current treatments targeting individual protein quality control pathways have limited efficacy in alleviating proteinopathies, highlighting the prerequisite for a common druggable target capable of global proteostasis modulation. Building upon our prior research establishing nuclear speckles as pivotal membrane-less organelles for transcriptional control of proteostasis, we aim to alleviate proteinopathies through nuclear speckle rehabilitation. We identify pyrvinium pamoate as a nuclear speckle rehabilitator that enhances protein quality control gene expression and suppresses YAP1 transcriptional activity via decreasing the surface/interfacial tension of nuclear speckle condensates through interaction with the intrinsically disordered region of nuclear speckle scaffold protein SON. In pre-clinical models, nanomolar pyrvinium pamoate protects against retinal degeneration and tauopathy mainly by promoting autophagy and ubiquitin-proteasome activity in a SON-dependent manner without causing stress. Aberrant nuclear speckle morphology, reduced protein quality control and increased YAP1 activity are observed in human tauopathies. Our study provides proof-of-principle of targeting nuclear speckles to ameliorate proteinopathies.
目前针对个体蛋白质质量控制途径的治疗方法在缓解蛋白质病方面疗效有限，这凸显了寻找一个能够全局调节蛋白质稳态的通用可药物靶点的必要性。基于我们之前的研究，即确定核斑点是蛋白质稳态转录控制的关键无膜细胞器，我们旨在通过修复核斑点来缓解蛋白质病。我们确定了帕莫酸吡维铵是一种核斑点修复剂，它通过与核斑点支架蛋白SON的内在无序区域相互作用，降低核斑点凝聚物的表面/界面张力，从而增强蛋白质质量控制基因的表达并抑制YAP1转录活性。在临床前模型中，纳摩尔浓度的帕莫酸吡维铵主要通过以SON依赖的方式促进自噬和泛素-蛋白酶体活性来预防视网膜变性和tau蛋白病，且不会引起应激。在人类tau蛋白病中观察到核斑点形态异常、蛋白质质量控制降低和YAP1活性增加。我们的研究提供了靶向核斑点以改善蛋白质病的原理证明。
