SON-dependent nuclear speckle rehabilitation alleviates proteinopathies
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.
Authors
- Manhong Ye (ORCID: https://orcid.org/0000-0002-1969-4810)
- Silvia Liu (ORCID: https://orcid.org/0000-0002-1840-9520)
- William A. Dion (ORCID: https://orcid.org/0000-0002-7697-9433)
- Bokai Zhu (ORCID: https://orcid.org/0000-0003-0827-5757)
- Michelle Sun (ORCID: https://orcid.org/0009-0000-8371-5930)
- Xu Chen (ORCID: https://orcid.org/0000-0001-8926-3090)
- Haokun H Wang (ORCID: https://orcid.org/0009-0003-6279-8003)
- Shaohua Pi (ORCID: https://orcid.org/0000-0002-7549-8929)
- Bennett Van Houten (ORCID: https://orcid.org/0000-0002-4009-2478)
- Mads Larsen (ORCID: https://orcid.org/0000-0001-5361-0898)
- Matthew A. Schaich (ORCID: https://orcid.org/0000-0001-6771-5623)
- Yuhang Nie
- Bill B. Chen (ORCID: https://orcid.org/0000-0003-2695-5107)
- Syeda Kubra
- Yuanyuan Chen (ORCID: https://orcid.org/0000-0001-9625-1610)
- Shanshan Zhao (ORCID: https://orcid.org/0000-0003-4083-1717)
- Bingjie Wang (ORCID: https://orcid.org/0000-0001-5056-7476)
- Riley K. Arbuckle (ORCID: https://orcid.org/0000-0002-7350-7967)
- Maci Chambers
- Chris Dupont
- Daniel P. Camarco (ORCID: https://orcid.org/0000-0001-7958-0658)
- Yuren Tao
- Imran Jamal
- Eleanor Ickes (ORCID: https://orcid.org/0009-0005-4561-7228)
Institutions
- University of Pittsburgh (US)
- University of California San Diego (US)
- UPMC Health System (US)
- UPMC Hillman Cancer Center (US)
- University of Pittsburgh Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-05
- DOI
- https://doi.org/10.1038/s41467-025-62242-7
- Citations
- 5
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 5.76
Funders
- Andrew W. Mellon Foundation
- Richard King Mellon Foundation
- Foundation Fighting Blindness
- Eye and Ear Foundation of Pittsburgh
- Research to Prevent Blindness
- University of Pittsburgh
- National Institutes of Health
- Center for Research Computing, University of Pittsburgh
- National Institute on Aging
- National Heart, Lung, and Blood Institute
- NIH Office of the Director
- National Eye Institute
- National Institute of General Medical Sciences
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Environmental Health Sciences