Small-molecule dissolution of stress granules by redox modulation benefits ALS models
Neurodegenerative diseases, such as amyotrophic lateral sclerosis, are often associated with mutations in stress granule proteins. Aberrant stress granule condensate formation is associated with disease, making it a potential target for pharmacological intervention. Here, we identified lipoamide, a small molecule that specifically prevents cytoplasmic condensation of stress granule proteins. Thermal proteome profiling showed that lipoamide stabilizes intrinsically disordered domain-containing proteins, including SRSF1 and SFPQ, which are stress granule proteins necessary for lipoamide activity. SFPQ has redox-state-specific condensate dissolving behavior, which is modulated by the redox-active lipoamide dithiolane ring. In animals, lipoamide ameliorates aging-associated aggregation of a stress granule reporter protein, improves neuronal morphology and recovers motor defects caused by amyotrophic lateral sclerosis-associated FUS and TDP-43 mutants. Thus, lipoamide is a well-tolerated small-molecule modulator of stress granule condensation, and dissection of its molecular mechanism identified a cellular pathway for redox regulation of stress granule formation.
Authors
- Satoshi Kishigami (ORCID: https://orcid.org/0000-0001-9447-5100)
- Ina Poser (ORCID: https://orcid.org/0000-0002-9108-1592)
- António Miguel de Jesus Domingues (ORCID: https://orcid.org/0000-0002-1803-1863)
- Florian Stengel (ORCID: https://orcid.org/0000-0003-1447-4509)
- Mikhail M. Savitski (ORCID: https://orcid.org/0000-0003-2011-9247)
- Simon Alberti (ORCID: https://orcid.org/0000-0003-4017-6505)
- Virgínia Casablancas-Antràs (ORCID: https://orcid.org/0000-0003-0892-6433)
- Anatol W. Fritsch (ORCID: https://orcid.org/0000-0003-0986-7068)
- Marcus Jahnel (ORCID: https://orcid.org/0000-0002-8355-277X)
- Marc Bickle (ORCID: https://orcid.org/0000-0002-8918-1869)
- Julius Fürsch
- Juan Manuel Iglesias‐Artola (ORCID: https://orcid.org/0000-0002-0409-795X)
- Hyun O. Lee (ORCID: https://orcid.org/0000-0003-0102-4795)
- Benjamin G. Davis (ORCID: https://orcid.org/0000-0002-5056-407X)
- Nadine Tomschke
- Richard John Wheeler (ORCID: https://orcid.org/0000-0002-4270-8360)
- Eric N. Anderson (ORCID: https://orcid.org/0000-0003-2533-8764)
- Arun Pal
- Andreas Hermann (ORCID: https://orcid.org/0000-0002-7364-7791)
- Anthony A. Hyman (ORCID: https://orcid.org/0000-0003-0851-704X)
- Frank Stein (ORCID: https://orcid.org/0000-0001-9695-1692)
- Edgar E. Boczek
- Udai Bhan Pandey (ORCID: https://orcid.org/0000-0002-6267-0179)
- Nicolas Lux Fawzi (ORCID: https://orcid.org/0000-0001-5483-0577)
- Jik Nijssen (ORCID: https://orcid.org/0000-0003-0013-9750)
- Della David (ORCID: https://orcid.org/0000-0001-8597-9470)
- Sukhleen Kour (ORCID: https://orcid.org/0000-0002-8068-5278)
- Hiroyuki Uechi (ORCID: https://orcid.org/0000-0002-7511-3558)
- Sindhuja Sridharan (ORCID: https://orcid.org/0000-0003-4548-2624)
- André Nadler (ORCID: https://orcid.org/0000-0001-6329-3910)
- Andrew J. Baldwin (ORCID: https://orcid.org/0000-0001-7579-8844)
- Anastasia C. Murthy (ORCID: https://orcid.org/0000-0002-2490-697X)
- Jessica Bilstein (ORCID: https://orcid.org/0009-0008-5627-2079)
- Thom Doeleman (ORCID: https://orcid.org/0000-0003-4568-9510)
- Xiaojie Zhang (ORCID: https://orcid.org/0000-0002-5946-7874)
- Eduardo J. Martinez
- Michael Wagner
Institutions
- Roche (Switzerland) (CH)
- Babraham Institute (GB)
- Queen Mary University of London (GB)
- University of Pittsburgh (US)
- University of Toronto (CA)
- University of Konstanz (DE)
- Tohoku University (JP)
- Brown University (US)
- German Center for Neurodegenerative Diseases (DE)
- Helmholtz-Zentrum Dresden-Rossendorf (DE)
- ShanghaiTech University (CN)
- University of Oxford (GB)
- Medawar Building for Pathogen Research (GB)
- Rosalind Franklin Institute (GB)
- Centre for Immunity, Infection and Evolution (GB)
- Children's Hospital of Pittsburgh (US)
- University of Pittsburgh Medical Center (US)
- European Molecular Biology Laboratory (DE)
- Center for Systems Biology Dresden (DE)
- Max Planck Institute of Molecular Cell Biology and Genetics (DE)
- University Hospital Carl Gustav Carus (DE)
- University of Rostock (DE)
- Technische Universität Dresden (DE)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature Chemical Biology
- Published
- 2025-05-14
- DOI
- https://doi.org/10.1038/s41589-025-01893-5
- Citations
- 29
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 40.29