Small molecule modulation of a redox-sensitive stress granule protein dissolves stress granules with beneficial outcomes for familial amyotrophic lateral sclerosis models

Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) are often associated with mutations in proteins that are associated with stress granules. Stress granules are condensates formed by liquid-liquid phase separation which, when aberrant, can lead to altered condensation behaviours and disease phenotypes. Here, we identified lipoamide, a small molecule which specifically prevents cytoplasmic condensation of stress granule proteins. Thermal proteome profiling showed that lipoamide preferentially stabilises intrinsically disordered domain-containing proteins. These include SRSF1 and SFPQ, stress granule proteins necessary for lipoamide activity. The redox state of SFPQ correlates with its condensate-dissolving behaviour, in concordance with the importance of the dithiolane ring for lipoamide activity. In animals, lipoamide ameliorates aging-associated aggregation of a stress granule reporter, improves neuronal morphology, and recovers motor defects caused by expression of ALS-associated FUS and TDP-43 mutants. In conclusion, 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. ### Competing Interest Statement Anthony Hyman is the Scientific Founder of Dewpoint Therapeutics; Anthony Hyman and Simon Alberti are Dewpoint Therapeutics shareholders; Richard Wheeler is a Scientific Advisor for Dewpoint Therapeutics; Antonio M. de Jesus Domingues is an employee of Dewpoint Therapeutics, but his contribution was prior to his employment. Anthony Hyman, Mark Bickle and Richard Wheeler filed a patent related to this work (US20200150107A1 and synchronized worldwide applications). Dewpoint Therapeutics contributed intellectually to this work in the structure-activity relationship analysis of lipoamide analogs. All other experimental work either predates foundation of Dewpoint Therapeutics or was carried out independently.