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

ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function. Murakami, T., Qamar, S., Lin, J., Q., Schierle, G., S., K., Rees, E., Miyashita, A., Costa, A., R., Dodd, R., B., Chan, F., T., S., Michel, C., H., Kronenberg-Versteeg, D., Li, Y., Yang, S., P., Wakutani, Y., Meadows, W., Ferry, R., R., Dong, L., Tartaglia, G., G., Favrin, G., Lin, W., L., Dickson, D., W., Zhen, M., Ron, D., Schmitt-Ulms, G., Fraser, P., E., Shneider, N., A., Holt, C., Vendruscolo, M., Kaminski, C., F., & St George-Hyslop, P. Neuron, 88(4):678-690, Cell Press, 2015.

Paper abstract bibtex

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

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 abstract = {The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a. C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins. Murakami et al. show that FUS transitions between monomer, liquid droplet, and hydrogel states during uptake and release of RNP granule cargo. FUS mutations accelerate transition into fibrillar hydrogels that trap RNP cargo, impair RNP granule function, and cause neurodegeneration.},
 bibtype = {article},
 author = {Murakami, Tetsuro and Qamar, Seema and Lin, Julie Qiaojin and Schierle, Gabriele S Kaminski and Rees, Eric and Miyashita, Akinori and Costa, Ana R. and Dodd, Roger B. and Chan, Fiona T S and Michel, Claire H. and Kronenberg-Versteeg, Deborah and Li, Yi and Yang, Seung Pil and Wakutani, Yosuke and Meadows, William and Ferry, Rodylyn Rose and Dong, Liang and Tartaglia, Gian Gaetano and Favrin, Giorgio and Lin, Wen Lang and Dickson, Dennis W. and Zhen, Mei and Ron, David and Schmitt-Ulms, Gerold and Fraser, Paul E. and Shneider, Neil A. and Holt, Christine and Vendruscolo, Michele and Kaminski, Clemens F. and St George-Hyslop, Peter},
 journal = {Neuron},
 number = {4}
}

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