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<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>in vitro</jats:italic>. More significantly, they also prevented aggregation of proteins over the life time of <jats:italic>Caenorhabditis elegans</jats:italic>. Observations that they prevent dieback of ALS patient-derived (FUS mutant) motor neuron axons in culture and recover motor defects in <jats:italic>Drosophila melanogaster</jats:italic> 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.</jats:p>

Original publication

DOI

10.1101/721001

Type

Journal article

Publisher

Cold Spring Harbor Laboratory

Publication Date

06/08/2019