The toxic activity of FUS, a protein linked to both amyotrophic sclerosis and frontotemporal dementia, may come down to a question of liquids versus solids. Today in Neuron, researchers led by Peter St. George-Hyslop of the University of Cambridge in England and the University of Toronto, Canada, report that the free-floating protein can condense first into liquids, then into two kinds of progressively thicker hydrogels containing fibrils.
The new paper joins several recent studies finding that FUS, as well as the neurodegeneration-linked protein hnRNPA1, condense much like the morning dew into non-membrane-bound organelles that house RNAs and associated proteins (see September 2015 news; October 2015 news).
The paper published in Neuron reflects four years’ worth of work by co-first authors Tetsuro Murakami of the University of Toronto, and Seema Qamar, Julie Qiaojin Lin, and Gabriele Schierle of the University of Cambridge, and colleagues. They analyzed wild-type and mutant FUS in vitro, in nematodes, and in cultured cells to delineate four possible protein phases. Two are relatively fluid: Individual FUS molecules can move individually, in a manner akin to gaseous particles, or condense into liquid-like droplets. These liquids hold in RNAs and their associated proteins, thus creating RNA-storing organelles such as stress granules.
Further, the liquid can turn into two phases of hydrogel, watery substances held together by polymers. One was reversible, and thus not dangerous for the cell, but the other was irreversible and toxic. FUS mutations that cause neurodegeneration prod the protein toward the most viscous—and vicious—state, though wild-type FUS can also solidify past the point of no return.
The authors posit that the reversible hydrogels may benefit the cell by stabilizing the liquid organelles. The permanent fibrils, however, were toxic to nematodes and cells. In part, this was explained by their propensity to ensnare other RNA-processing proteins including, notably, those required for protein synthesis in axon terminals.
Murakami T, Qamar S, Lin JQ, Schierle GS, Rees E, Miyashita A, Costa AR, Dodd RB, Chan FT, Michel CH, Kronenberg-Versteeg D, Li Y, Yang SP, Wakutani Y, Meadows W, Ferry RR, Dong L, Tartaglia GG, Favrin G, Lin WL, Dickson DW, Zhen M, Ron D, Schmitt-Ulms G, Fraser PE, Shneider NA, Holt C, Vendruscolo M, Kaminski CF, St George-Hyslop P. ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function. Neuron. 2015 Nov 18;88(4):678-90. Epub 2015 Oct 29 PubMed.
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