Small molecules for modulating protein driven liquid-liquid phase separation in treating neurodegenerative disease

Wheeler, R. J.; Lee, H. O.; Poser, I.; Pal, A.; Doeleman, T.; Kishigami, S.; Kour, S.; Anderson, E. N.; Marrone, L.; Murthy, A. C.; Jahnel, M.; Zhang, X.; Boczek, E.; Fritsch, A.; Fawzi, N. L.; Sterneckert, J.; Pandey, U.; David, D. C.; Davis, B. G.; Baldwin, A. J.; Hermann, A.; Bickle, M.; Alberti, S.; Hyman, A. A.

doi:10.1101/721001

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bioRxiv · 10.1101/721001

Small molecules for modulating protein driven liquid-liquid phase separation in treating neurodegenerative disease

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Abstract

Neurodegenerave diseases such as amyotrophic lateral sclerosis (ALS) are oten associated with mutaons in proteins that are associated with stress granules. Stress granules are condensates formed by liquid-liquid phase separaon which, when aberrant, can lead to altered condensaon behaviours and disease phenotypes. Here, we identified lipoamide, a small molecule which specifically prevents cytoplasmic condensaon 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 aggregaon 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 condensaon and dissection of its molecular mechanism identified a cellular pathway for redox regulaon of stress granule formaon.

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Wheeler, R. J., Lee, H. O., Poser, I., Pal, A., Doeleman, T., Kishigami, S., Kour, S., Anderson, E. N., Marrone, L., Murthy, A. C., Jahnel, M., Zhang, X., Boczek, E., Fritsch, A., Fawzi, N. L., Sterneckert, J., Pandey, U., David, D. C., Davis, B. G., Baldwin, A. J., Hermann, A., Bickle, M., Alberti, S., Hyman, A. A.. 2019-08-05. Small molecules for modulating protein driven liquid-liquid phase separation in treating neurodegenerative disease. https://doi.org/10.1101/721001

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