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000281502 1001_ $$00000-0002-7511-3558$$aUechi, Hiroyuki$$b0
000281502 245__ $$aSmall-molecule dissolution of stress granules by redox modulation benefits ALS models.
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000281502 520__ $$aNeurodegenerative diseases, such as amyotrophic lateral sclerosis, are often associated with mutations in stress granule proteins. Aberrant stress granule condensate formation is associated with disease, making it a potential target for pharmacological intervention. Here, we identified lipoamide, a small molecule that specifically prevents cytoplasmic condensation of stress granule proteins. Thermal proteome profiling showed that lipoamide stabilizes intrinsically disordered domain-containing proteins, including SRSF1 and SFPQ, which are stress granule proteins necessary for lipoamide activity. SFPQ has redox-state-specific condensate dissolving behavior, which is modulated by the redox-active lipoamide dithiolane ring. In animals, lipoamide ameliorates aging-associated aggregation of a stress granule reporter protein, improves neuronal morphology and recovers motor defects caused by amyotrophic lateral sclerosis-associated FUS and TDP-43 mutants. Thus, lipoamide is a well-tolerated small-molecule modulator of stress granule condensation, and dissection of its molecular mechanism identified a cellular pathway for redox regulation of stress granule formation.
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000281502 650_7 $$2NLM Chemicals$$aSmall Molecule Libraries
000281502 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000281502 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: drug therapy
000281502 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000281502 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: pathology
000281502 650_2 $$2MeSH$$aOxidation-Reduction: drug effects
000281502 650_2 $$2MeSH$$aHumans
000281502 650_2 $$2MeSH$$aAnimals
000281502 650_2 $$2MeSH$$aStress Granules: metabolism
000281502 650_2 $$2MeSH$$aStress Granules: drug effects
000281502 650_2 $$2MeSH$$aSmall Molecule Libraries: pharmacology
000281502 650_2 $$2MeSH$$aSmall Molecule Libraries: chemistry
000281502 650_2 $$2MeSH$$aMice
000281502 650_2 $$2MeSH$$aDisease Models, Animal
000281502 7001_ $$00000-0003-4548-2624$$aSridharan, Sindhuja$$b1
000281502 7001_ $$00000-0003-0013-9750$$aNijssen, Jik$$b2
000281502 7001_ $$00009-0008-5627-2079$$aBilstein, Jessica$$b3
000281502 7001_ $$00000-0002-0409-795X$$aIglesias-Artola, Juan M$$b4
000281502 7001_ $$aKishigami, Satoshi$$b5
000281502 7001_ $$00000-0003-0892-6433$$aCasablancas-Antras, Virginia$$b6
000281502 7001_ $$aPoser, Ina$$b7
000281502 7001_ $$aMartinez, Eduardo J$$b8
000281502 7001_ $$aBoczek, Edgar$$b9
000281502 7001_ $$0P:(DE-HGF)0$$aWagner, Michael$$b10
000281502 7001_ $$aTomschke, Nadine$$b11
000281502 7001_ $$00000-0002-1803-1863$$ade Jesus Domingues, António M$$b12
000281502 7001_ $$aPal, Arun$$b13
000281502 7001_ $$00000-0003-4568-9510$$aDoeleman, Thom$$b14
000281502 7001_ $$00000-0002-8068-5278$$aKour, Sukhleen$$b15
000281502 7001_ $$aAnderson, Eric Nathaniel$$b16
000281502 7001_ $$00000-0001-9695-1692$$aStein, Frank$$b17
000281502 7001_ $$0P:(DE-HGF)0$$aLee, Hyun O$$b18
000281502 7001_ $$00000-0002-5946-7874$$aZhang, Xiaojie$$b19
000281502 7001_ $$aFritsch, Anatol W$$b20
000281502 7001_ $$aJahnel, Marcus$$b21
000281502 7001_ $$aFürsch, Julius$$b22
000281502 7001_ $$00000-0002-2490-697X$$aMurthy, Anastasia C$$b23
000281502 7001_ $$00000-0003-4017-6505$$aAlberti, Simon$$b24
000281502 7001_ $$00000-0002-8918-1869$$aBickle, Marc$$b25
000281502 7001_ $$00000-0001-5483-0577$$aFawzi, Nicolas L$$b26
000281502 7001_ $$00000-0001-6329-3910$$aNadler, André$$b27
000281502 7001_ $$0P:(DE-2719)2810353$$aDavid, Della C$$b28
000281502 7001_ $$00000-0002-6267-0179$$aPandey, Udai B$$b29
000281502 7001_ $$0P:(DE-2719)2811732$$aHermann, Andreas$$b30$$udzne
000281502 7001_ $$00000-0003-1447-4509$$aStengel, Florian$$b31
000281502 7001_ $$00000-0002-5056-407X$$aDavis, Benjamin G$$b32
000281502 7001_ $$00000-0001-7579-8844$$aBaldwin, Andrew J$$b33
000281502 7001_ $$00000-0003-2011-9247$$aSavitski, Mikhail M$$b34
000281502 7001_ $$00000-0003-0851-704X$$aHyman, Anthony A$$b35
000281502 7001_ $$00000-0002-4270-8360$$aWheeler, Richard J$$b36
000281502 773__ $$0PERI:(DE-600)2190276-8$$a10.1038/s41589-025-01893-5$$gVol. 21, no. 10, p. 1577 - 1588$$n10$$p1577 - 1588$$tNature chemical biology$$v21$$x1552-4450$$y2025
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