Small-molecule dissolution of stress granules by redox modulation benefits ALS models
Hiroyuki Uechi, Sindhuja Sridharan, Jik Nijssen, Jessica Bilstein, Juan M. Iglesias‐Artola, Satoshi Kishigami, Virgínia Casablancas-Antràs, Ina Poser, Eduardo J. Martinez, Edgar E. Boczek, Michael Wagner, Nadine Tomschke, António Miguel de Jesus Domingues, Arun Pal, Thom Doeleman, Sukhleen Kour, Eric N. Anderson, Frank Stein, Hyun O. Lee, Xiaojie Zhang, Anatol W. Fritsch, Marcus Jahnel, Julius Fürsch, Anastasia C. Murthy, Simon Alberti, Marc Bickle, Nicolas L. Fawzi, André Nadler, Della David, Udai Bhan Pandey, Andreas Hermann, Florian Stengel, Benjamin G. Davis, Andrew J. Baldwin, Mikhail M. Savitski, Anthony A. Hyman, Richard John Wheeler
Abstract
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.