PT  - JOURNAL ARTICLE
AU  - Richard J. Wheeler
AU  - Hyun O. Lee
AU  - Ina Poser
AU  - Arun Pal
AU  - Thom Doeleman
AU  - Satoshi Kishigami
AU  - Sukhleen Kour
AU  - Eric Nathaniel Anderson
AU  - Lara Marrone
AU  - Anastasia C. Murthy
AU  - Marcus Jahnel
AU  - Xiaojie Zhang
AU  - Edgar Boczek
AU  - Anatol Fritsch
AU  - Nicolas L. Fawzi
AU  - Jared Sterneckert
AU  - Udai Pandey
AU  - Della C. David
AU  - Benjamin G. Davis
AU  - Andrew J. Baldwin
AU  - Andreas Hermann
AU  - Marc Bickle
AU  - Simon Alberti
AU  - Anthony A. Hyman
TI  - Small molecules for modulating protein driven liquid-liquid phase separation in treating neurodegenerative disease
AID  - 10.1101/721001
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 721001
4099  - http://biorxiv.org/content/early/2019/08/21/721001.short
4100  - http://biorxiv.org/content/early/2019/08/21/721001.full
AB  - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with few avenues for treatment. Many proteins implicated in ALS associate with stress granules, which are examples of liquid-like compartments formed by phase separation. Aberrant phase transition of stress granules has been implicated in disease, suggesting that modulation of phase transitions could be a possible therapeutic route. Here, we combine cell-based and protein-based screens to show that lipoamide, and its related compound lipoic acid, reduce the propensity of stress granule proteins to aggregate in vitro. More significantly, they also prevented aggregation of proteins over the life time of Caenorhabditis elegans. Observations that they prevent dieback of ALS patient-derived (FUS mutant) motor neuron axons in culture and recover motor defects in Drosophila melanogaster expressing FUS mutants suggest plausibility as effective therapeutics. Our results suggest that altering phase behaviour of stress granule proteins in the cytoplasm could be a novel route to treat ALS.