SON-dependent nuclear speckle rehabilitation alleviates proteinopathies
Authors:
- Matthew A. SchaichMSMatthew A. Schaich
- Imran JamalIJImran Jamal
Preprint
Abstract
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 identified 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 protected 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 were observed in human tauopathies. Our study provides proof-of-principle of targeting nuclear speckles to ameliorate proteinopathies.Keywords
All Related Versions
- Published version: Nature Communications, 16 (1), 1.
This publication has 118 references indexed in Scilit:
- Beyond circadian rhythms: emerging roles of ultradian rhythms in control of liver functionsHepatology, 2023
- Revealing the hidden reality of the mammalian 12-h ultradian rhythmsCellular and Molecular Life Sciences, 2021
- Measuring Protein Synthesis in Cultured Cells and Mouse Tissues Using the Non‐radioactive SUnSET AssayCurrent Protocols in Molecular Biology, 2020
- Speculating on the Roles of Nuclear Speckles: How RNA‐Protein Nuclear Assemblies Affect Gene ExpressionBioEssays, 2020
- Mutations in REEP6 Cause Autosomal-Recessive Retinitis PigmentosaThe American Journal of Human Genetics, 2016
- Robust Endoplasmic Reticulum-Associated Degradation of Rhodopsin Precedes Retinal DegenerationMolecular Neurobiology, 2014
- The role of SON in splicing, development, and diseaseWIREs RNA, 2014
- Transformed Drosophila Cells Evade Diet-Mediated Insulin Resistance through Wingless SignalingCell, 2013
- Protein Quality Control in Neurodegenerative Disease2012
- The commonly used marker ELAV is transiently expressed in neuroblasts and glial cells in the Drosophila embryonic CNSDevelopmental Dynamics, 2007