ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function

• DOI: 10.1016/j.neuron.2015.10.030
• Publication Date: 2015-11-03T09:10:41Z
• Authors: Tetsuro Murakami; Seema Qamar; Julie Qiaojin Lin; Gabriele S. Kamin...; Eric Rees; Akinori Miyashita; Ana R. Costa; Roger B. Dodd; Fiona T.S. Chan; Claire H. Michel; Deborah Kronenber...; Yi Li; Seung-Pil Yang; Yosuke Wakutani; William Meadows; Rodylyn Rose Ferry; Liang Dong; Gian Gaetano Tart...; Giorgio Favrin; Wen-Lang Lin; Dennis W. Dickson; Mei Zhen; David Ron; Gerold Schmitt-Ulms; Paul E. Fraser; Neil A. Shneider; Christine Holt; Michele Vendruscolo; Clemens F. Kaminski; Peter St George-H...
• Keywords: Stress granule; Neurotoxicity; Granule (geology)

The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS FTD remain controversial. We propose a model low-complexity (LC) domains of drive its physiologically reversible assembly into membrane-free, liquid droplet hydrogel-like structures. ALS/FTD LC or non-LC induce further phase transition poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary sufficient for neurotoxicity C. elegans FUS-dependent neurodegeneration. They trap ribonucleoprotein (RNP) granule components disrupt RNP function. One consequence is impairment new protein synthesis cytoplasmic granules axon terminals, where regulate local metabolism translation. Nuclear may be similarly affected. Inhibiting formation these hydrogel mitigates suggests potential therapeutic strategy that also applicable to associated with proteins.