Abstract
Neurodegeneràve diseases such as amyotrophic lateral sclerosis (ALS) are oten associated with mutàons in proteins that are associated with stress granules. Stress granules are condensates formed by liquid-liquid phase separàon which, when aberrant, can lead to altered condensàon behaviours and disease phenotypes. Here, we identified lipoamide, a small molecule which specifically prevents cytoplasmic condensàon 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 aggregàon 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 condensàon and dissection of its molecular mechanism identified a cellular pathway for redox regulàon of stress granule formàon.
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.
Footnotes
↵# uechi{at}mpi-cbg.de, sindhuja.sridharan{at}embl.de, nijssen{at}mpi-cbg.de, jessica.bellmann{at}uniklinikum-dresden.de, jiglesia{at}mpi-cbg.de, satoshi.kishigami{at}exeter.ox.ac.uk, virginia.casablancasantras{at}st-annes.ox.ac.uk, iposer{at}dewpointx.com, emartinez{at}dewpointx.com, eboczek{at}dewpointtherapeutics.com, mwagner{at}dewpointx.com, tomschke{at}mpi-cbg.de, amjdomingues{at}gmail.com, a.pal{at}hzdr.de, T.Doeleman-3{at}umcutrecht.nl, suk106{at}piU.edu ena15{at}piU.edu frank.stein{at}embl.de, hyunokate.lee{at}utoronto.ca, zhangxj2{at}shanghaitech.edu.cn, fritsch{at}mpi-cbg.de, marcus.jahnel{at}tu-dresden.de, juliusfuersch{at}gmail.com, anastasia_murthy{at}alumni.brown.edu, simon.alberti{at}tu-dresden.de marc.bickle{at}roche.com, nicolas_fawzi{at}brown.edu, nadler{at}mpi-cbg.de, della.david{at}babraham.ac.uk, udai{at}piU.edu, Andreas.Hermann{at}med.uni-rostock.de, florian.stengel{at}uni-konstanz.de, ben.davis{at}chem.ox.ac.uk, andrew.baldwin{at}chem.ox.ac.uk mikhail.savitski{at}embl.de hyman{at}mpi-cbg.de, richard.wheeler{at}ndm.ox.ac.uk
Comprehensive revision and extension based on several large additional experimental strategies.