%0 Journal Article
%A Uechi, Hiroyuki
%A Sridharan, Sindhuja
%A Nijssen, Jik
%A Bilstein, Jessica
%A Iglesias-Artola, Juan M
%A Kishigami, Satoshi
%A Casablancas-Antras, Virginia
%A Poser, Ina
%A Martinez, Eduardo J
%A Boczek, Edgar
%A Wagner, Michael
%A Tomschke, Nadine
%A de Jesus Domingues, António M
%A Pal, Arun
%A Doeleman, Thom
%A Kour, Sukhleen
%A Anderson, Eric Nathaniel
%A Stein, Frank
%A Lee, Hyun O
%A Zhang, Xiaojie
%A Fritsch, Anatol W
%A Jahnel, Marcus
%A Fürsch, Julius
%A Murthy, Anastasia C
%A Alberti, Simon
%A Bickle, Marc
%A Fawzi, Nicolas L
%A Nadler, André
%A David, Della C
%A Pandey, Udai B
%A Hermann, Andreas
%A Stengel, Florian
%A Davis, Benjamin G
%A Baldwin, Andrew J
%A Savitski, Mikhail M
%A Hyman, Anthony A
%A Wheeler, Richard J
%T Small-molecule dissolution of stress granules by redox modulation benefits ALS models.
%J Nature chemical biology
%V 21
%N 10
%@ 1552-4450
%C Basingstoke
%I Nature Publishing Group
%M DZNE-2025-01123
%P 1577 - 1588
%D 2025
%X 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.
%K Amyotrophic Lateral Sclerosis: metabolism
%K Amyotrophic Lateral Sclerosis: drug therapy
%K Amyotrophic Lateral Sclerosis: genetics
%K Amyotrophic Lateral Sclerosis: pathology
%K Oxidation-Reduction: drug effects
%K Humans
%K Animals
%K Stress Granules: metabolism
%K Stress Granules: drug effects
%K Small Molecule Libraries: pharmacology
%K Small Molecule Libraries: chemistry
%K Mice
%K Disease Models, Animal
%K Small Molecule Libraries (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40369342
%2 pmc:PMC12463676
%R 10.1038/s41589-025-01893-5
%U https://pub.dzne.de/record/281502