Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains.

Authors

Lin Guo, Thomas Jefferson UniversityFollow
Jacob Mann
Jocelyn Mauna
Katie Copley
Hejia Wang
Jack Rubien
Cristian Bergmann
Jenny Carey, Thomas Jefferson UniversityFollow
Jessica Merjane
Marilyn Ngo
Jiazhen Xu
Hana Odeh
JiaBei Lin
Bo Lim Lee
Laura Ganser
Emma Robinson, Thomas Jefferson University
Kevin Kim
Anastasia Murthy
Tapas Paul
Bede Portz
Amanda Gleixner
Zamia Diaz
Ashleigh Smirnov
George Padilla
Ellen Lavorando
Carolann Espy
Yulei Shang
Eric Huang
Alessandra Chesi
Nicolas Fawzi
Sua Myong
Christopher Donnelly
James Shorter

Document Type

Article

Publication Date

1-8-2026

Comments

This article is the author’s final published version in Molecular Cell, Volume 86, Issue 1, 2025, Pages 114-134.e10.

The published version is available at https://doi.org/10.1016/j.molcel.2025.12.009. Copyright ©  2025 The Author(s).

Abstract

RNA-binding proteins (RBPs) with prion-like domains (PrLDs), such as FUS and TDP-43, condense into functional liquids, which can transform into pathological fibrils that underpin fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). Here, we define short RNAs that prevent FUS fibrillization by promoting liquid phases and distinct short RNAs that prevent and reverse FUS condensation and fibrillization. These activities require interactions with multiple RNA-binding domains of FUS and are encoded by RNA sequence, length, and structure. We define a short RNA that dissolves cytoplasmic FUS aggregates, restores nuclear FUS, and mitigates FUS toxicity in optogenetic models and ALS patient-derived motor neurons. Another short RNA dissolves cytoplasmic TDP-43 aggregates, restores nuclear TDP-43, and mitigates TDP-43 toxicity. Since short RNAs can be effectively delivered to the human brain, these oligonucleotides could have utility for ALS/FTD and related disorders.

Recommended Citation

Guo, Lin; Mann, Jacob; Mauna, Jocelyn; Copley, Katie; Wang, Hejia; Rubien, Jack; Bergmann, Cristian; Carey, Jenny; Merjane, Jessica; Ngo, Marilyn; Xu, Jiazhen; Odeh, Hana; Lin, JiaBei; Lee, Bo Lim; Ganser, Laura; Robinson, Emma; Kim, Kevin; Murthy, Anastasia; Paul, Tapas; Portz, Bede; Gleixner, Amanda; Diaz, Zamia; Smirnov, Ashleigh; Padilla, George; Lavorando, Ellen; Espy, Carolann; Shang, Yulei; Huang, Eric; Chesi, Alessandra; Fawzi, Nicolas; Myong, Sua; Donnelly, Christopher; and Shorter, James, "Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains." (2026). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 295.
https://jdc.jefferson.edu/bmpfp/295

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

PubMed ID

41512823

Language

English