Home > Publications Database > Small-molecule dissolution of stress granules by redox modulation benefits ALS models. > print

001     281502
005     20251102002041.0
024 7 _ |a 10.1038/s41589-025-01893-5
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037 _ _ |a DZNE-2025-01123
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082 _ _ |a 570
100 1 _ |a Uechi, Hiroyuki
|0 0000-0002-7511-3558
|b 0
245 _ _ |a Small-molecule dissolution of stress granules by redox modulation benefits ALS models.
260 _ _ |a Basingstoke
|c 2025
|b Nature Publishing Group
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520 _ _ |a 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.
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650 _ 7 |a Small Molecule Libraries
|2 NLM Chemicals
650 _ 2 |a Amyotrophic Lateral Sclerosis: metabolism
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: drug therapy
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: genetics
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: pathology
|2 MeSH
650 _ 2 |a Oxidation-Reduction: drug effects
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Stress Granules: metabolism
|2 MeSH
650 _ 2 |a Stress Granules: drug effects
|2 MeSH
650 _ 2 |a Small Molecule Libraries: pharmacology
|2 MeSH
650 _ 2 |a Small Molecule Libraries: chemistry
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
700 1 _ |a Sridharan, Sindhuja
|0 0000-0003-4548-2624
|b 1
700 1 _ |a Nijssen, Jik
|0 0000-0003-0013-9750
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700 1 _ |a Bilstein, Jessica
|0 0009-0008-5627-2079
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700 1 _ |a Iglesias-Artola, Juan M
|0 0000-0002-0409-795X
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700 1 _ |a Kishigami, Satoshi
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700 1 _ |a Casablancas-Antras, Virginia
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700 1 _ |a Poser, Ina
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700 1 _ |a Martinez, Eduardo J
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700 1 _ |a Boczek, Edgar
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700 1 _ |a Wagner, Michael
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700 1 _ |a Tomschke, Nadine
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700 1 _ |a de Jesus Domingues, António M
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700 1 _ |a Pal, Arun
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700 1 _ |a Doeleman, Thom
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700 1 _ |a Kour, Sukhleen
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700 1 _ |a Anderson, Eric Nathaniel
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700 1 _ |a Stein, Frank
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700 1 _ |a Lee, Hyun O
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700 1 _ |a Zhang, Xiaojie
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700 1 _ |a Fritsch, Anatol W
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700 1 _ |a Jahnel, Marcus
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700 1 _ |a Fürsch, Julius
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700 1 _ |a Murthy, Anastasia C
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700 1 _ |a Alberti, Simon
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700 1 _ |a Bickle, Marc
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700 1 _ |a Fawzi, Nicolas L
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700 1 _ |a Nadler, André
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700 1 _ |a David, Della C
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700 1 _ |a Hermann, Andreas
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700 1 _ |a Stengel, Florian
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700 1 _ |a Davis, Benjamin G
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700 1 _ |a Baldwin, Andrew J
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700 1 _ |a Savitski, Mikhail M
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700 1 _ |a Hyman, Anthony A
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700 1 _ |a Wheeler, Richard J
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773 _ _ |a 10.1038/s41589-025-01893-5
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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