ArticleMolecular cell2026
Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains.
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Article in Molecular cell, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed.
- Article
- Isoform-specific steric zippers drive aberrant assembly and mislocalization of shortened TDP-43.Science advances · 2026Article
- RNA G-quadruplexes function as a tunable switch of FUS phase separation.Nucleic acids research · 2026Article
- Noncoding RNAs are indispensable architects and regulators of biomolecular condensates.Non-coding RNA research · 2026Review
- Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration.Science (New York, N.Y.) · 2026Article
- Condensate State as Determinant of Amyloid Pathology in Neurodegeneration.Biomolecules · 2026Review
- Splicing the narrative: alternative TARDBP splicing and its relation to neurodegeneration in ALS and FTD.The Journal of clinical investigation · 2026Review
- Nuclear-import receptors remodel the dilute phase to suppress phase transitions of RNA-binding proteins with prion-like domains.bioRxiv : the preprint server for biology · 2025Article
- RNA G-Quadruplexes Function as a Tunable Switch of FUS Phase Separation.bioRxiv : the preprint server for biology · 2025Article
- Probing the Formation and Liquid-to-Solid Transition of FUS Condensates via the Lifetimes of Fluorescent Proteins.The journal of physical chemistry letters · 2025Article
- Context-dependent Interactors Regulate TDP-43 Dysfunction in ALS/FTLD.bioRxiv : the preprint server for biology · 2025Article
- Opposing roles of p38α-mediated phosphorylation and PRMT1-mediated arginine methylation in driving TDP-43 proteinopathy.Cell reports · 2025Article
- Design principles to tailor Hsp104 therapeutics.Cell reports · 2024Article
- A Hydrophobic Core Stabilizes the Residual Structure in the RRM2 Intermediate State of the ALS-linked Protein TDP-43.Journal of molecular biology · 2024Article
- Multivalent GU-rich oligonucleotides sequester TDP-43 in the nucleus by inducing high molecular weight RNP complexes.iScience · 2024Article
- Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD.Molecular neurodegeneration · 2024Review
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Authors and funding
33 authors.
Lin GuoDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA. Electronic address: lin.guo@jefferson.edu.
Jacob R MannDepartment of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Live Like Lou Center for ALS Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Protein Conformational Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Jocelyn C MaunaDepartment of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Live Like Lou Center for ALS Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Protein Conformational Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Katie E CopleyDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Hejia WangDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Jack D RubienDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Cristian A BergmannDepartment of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Live Like Lou Center for ALS Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Protein Conformational Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Jenny L CareyDepartment of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA.
Jessica MerjaneDepartment of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Live Like Lou Center for ALS Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Protein Conformational Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Marilyn NgoDepartment of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Live Like Lou Center for ALS Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Protein Conformational Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Jiazhen XuDepartment of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Live Like Lou Center for ALS Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Protein Conformational Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Hana M OdehDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
JiaBei LinDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Bo Lim LeeDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Laura GanserDepartment of Biophysics, Johns Hopkins University, Baltimore, MD, USA.
Emma RobinsonDepartment of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA.
Kevin M KimDepartment of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA.
Anastasia C MurthyDepartment of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI, USA.
Tapas PaulDepartment of Biophysics, Johns Hopkins University, Baltimore, MD, USA.
Bede PortzDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Amanda M GleixnerDepartment of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Live Like Lou Center for ALS Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Protein Conformational Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Zamia DiazDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Ashleigh SmirnovDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
George PadillaDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Ellen LavorandoDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Carolann EspyDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Yulei ShangEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
Eric J HuangEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
Alessandra ChesiDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Nicolas L FawziDepartment of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI, USA.
Sua MyongDepartment of Biophysics, Johns Hopkins University, Baltimore, MD, USA.
Christopher J DonnellyDepartment of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Live Like Lou Center for ALS Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Protein Conformational Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Institute for Neurodegeneration, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: cjdon25@pitt.edu.
James ShorterDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: jshorter@pennmedicine.upenn.edu.
Funding
Phenotypic Diversity in COVID-19UL1TR001878 · NCATS · UNIVERSITY OF PENNSYLVANIA · PI FITZGERALD, GARRET A · 2016 to 2025
$102.4MIdentification of TDP-43 Modifiers Through Single-Cell Transcriptional and Epigenomic Dissection of ALS and FTLD-MNDR01NS127187 · NINDS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI BELZIL, VERONIQUE, DONNELLY, CHRISTOPHER JAMES · 2021 to 2025
$9.1MTRAINING IN MOLECULAR &CELL BIOLOGY &BIOCHEMISTRYT32GM007601 · NIGMS · BROWN UNIVERSITY · PI MOWRY, KIMBERLY L. · 1985 to 2019
$6.4MTraining in the Neurobiology of Neurological DiseaseT32NS086749 · NINDS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Omar El Gharbawie, REBECCA P SEAL · 2014 to 2026
$4.8MFunctional and Pathological Interactions of TDP-43R01NS116176 · NINDS · BROWN UNIVERSITY · PI FAWZI, NICOLAS LUX, MITTAL, JEETAIN · 2020 to 2024
$3.6MDefining short RNA therapeutics that combat TDP-43 proteinopathy connected to AD and ADRDs.RF1AG090910 · NIA · UNIVERSITY OF PENNSYLVANIA · PI DONNELLY, CHRISTOPHER JAMES, KALB, ROBERT G · 2025 to 2025
$3.4MStructural biology and molecular biophysics training programT32GM132039 · NIGMS · UNIVERSITY OF PENNSYLVANIA · PI Ben E. Black, Elizabeth Rhoades · 2019 to 2026
$3.3MElucidating the Mechanism in the Regulation of RNA-binding Protein Phase SeparationR35GM138109 · NIGMS · THOMAS JEFFERSON UNIVERSITY · PI Lin Guo · 2020 to 2026
$2.6MRAD23 Control of ALS phenotypesR01NS122908 · NINDS · NORTHWESTERN UNIVERSITY AT CHICAGO · PI KALB, ROBERT G · 2021 to 2025
$2.0MAn optogenetic approach to establish the interplay between stress granules and TDP-43 proteinopathy in ALS/FTDR01NS105756 · NINDS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI DONNELLY, CHRISTOPHER JAMES · 2018 to 2022
$1.8MResidue-by-residue details of FUS protein phase separation and aggregationR01GM147677 · NIGMS · BROWN UNIVERSITY · PI FAWZI, NICOLAS LUX · 2022 to 2025
$1.7MDeveloping RNA Oligonucleotides to Mitigate Abberant FUS Phase Transition in FTD/ALSRF1NS121143 · NINDS · THOMAS JEFFERSON UNIVERSITY · PI GUO, LIN · 2021 to 2021
$1.2MNCATS NIH HHS UL1 TR001878NIA NIH HHS R21 AG064940NIA NIH HHS RF1 AG090910NIGMS NIH HHS R01 GM147677NIGMS NIH HHS R35 GM138109NIGMS NIH HHS T32 GM007601NIGMS NIH HHS T32 GM132039NINDS NIH HHS F31 NS129101NINDS NIH HHS R01 NS105756NINDS NIH HHS R01 NS116176NINDS NIH HHS R01 NS121143NINDS NIH HHS R01 NS122908NINDS NIH HHS R01 NS127187NINDS NIH HHS R21 NS133676NINDS NIH HHS RF1 NS121143NINDS NIH HHS T32 NS086749
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.
Indexed as
Amyotrophic Lateral SclerosisDNA-Binding ProteinsFrontotemporal DementiaOligonucleotidesPrionsRNARNA-Binding Protein FUSAnimalsHumansMotor NeuronsPhase TransitionProtein AggregatesProtein DomainsRNA-Binding ProteinsDNA-Binding ProteinsFUS protein, humanOligonucleotidesPrionsProtein AggregatesRNARNA-Binding Protein FUSRNA-Binding ProteinsTARDBP protein, humanALSdisaggregaseFTDFUSphase separationprion-like domainRNATDP-43
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