Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration
Open accessPublished version of a preprint
Abstract
Aberrant aggregation of the prion-like RNA binding protein TDP-43 drives several fatal neurodegenerative proteinopathies, including amyotrophic lateral sclerosis (ALS). In this work, we define how short, specific RNAs solubilize TDP-43. These short RNAs engage and stabilize the TDP-43 RNA recognition motifs, which allosterically destabilizes a conserved helical region in the prion-like domain, thereby promoting aggregation-resistant conformers. Sequence-space mining identified short RNA chaperones with enhanced activity against TDP-43 and disease-linked variants. Enhanced short RNA chaperones mitigated aberrant TDP-43 phenotypes in optogenetic models and in ALS patient–derived and control motor neurons. In mice with cytoplasmic TDP-43 aggregation and motor neuron loss, an enhanced short RNA chaperone reduced pathological aggregation, restored TDP-43 function, and conferred neuroprotection. These results define a mechanistic and therapeutic framework for RNA-based strategies to counter TDP-43 proteinopathies.
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- Authors
- Copley, K. E., Mauna, J. C., Danielson, H. L., Chen, Q., Ozguney, B., Ngo, M., Xie, L., Smirnov, A., Davis, M., Mayne, L., Linsenmeier, M., Rubien, J. D., Bergmann, C. A., Portz, B., Lee, B. L., Odeh, H. M., Lai, L., Chang, Y.-W., Hallegger, M., Ule, J., Pasinelli, P., Poon, Y., Mittal, J., Fawzi, N. L., Black, B. E., Donnelly, C. J., Jensen, B. K., & Shorter, J.
- Affiliations
- University of Pennsylvania (US)
- University of Pittsburgh (US)
- Brown University (US)
- Texas A&M University (US)
- Thomas Jefferson University (US)
- Centre for Human Genetics (GB)
- King's College London (GB)
- Confluence Therapeutics, San Francisco, CA, USA.
- Corresponding author
- Shorter, James
- ORCID
- Copley, Katie E.
- Mauna, Jocelyn C.
- Danielson, Helen L.
- Chen, Qizan
- Ozguney, Busra
- Ngo, Marilyn
- Xie, Longxin
- Smirnov, Ashleigh
- Davis, Matt
- Mayne, Leland
- Linsenmeier, Miriam
- Rubien, Jack D.
- Bergmann, Cristian A.
- Portz, Bede
- Lee, Bo Lim
- Odeh, Hana M.
- Chang, Yi-Wei
- Hallegger, Martina
- Ule, Jernej
- Pasinelli, Piera
- Mittal, Jeetain
- Fawzi, Nicolas L.
- Black, Ben E.
- Donnelly, Christopher J.
- Jensen, Brigid K.
- Shorter, James
- Venue
- Science
- Published
- 2026-05-07
- Volume
- 392
- Issue
- 6798
- Pages
- eadv3301-eadv3301
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W4405976212
- Cited by
- 16
- References
- 8
- Citations by year
- 2026: 13 · 2025: 3
- FWCI
- 55.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Science (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Institutes of Health (F31NS129101, RF1AG090910)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- TDP-43, RNA chaperone, RNA therapeutics, protein aggregation, amyotrophic lateral sclerosis, prion-like domains, RNA recognition motif, neurodegeneration, motor neurons, neuroprotection
- MeSH terms
- RNA Recognition Motif, Amyotrophic Lateral Sclerosis, Animals, DNA-Binding Proteins, Humans, Motor Neurons, RNA, Mice, TDP-43 Proteinopathies, Protein Aggregation, Pathological
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