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

Tetsuro Murakami, Seema Qamar, Julie Qiaojin Lin, Gabriele S Kaminski Schierle, Eric Rees, Akinori Miyashita, Ana R. Costa, Roger B. Dodd, Fiona T S Chan, Claire H. Michel, Deborah Kronenberg-Versteeg, Yi Li, Seung Pil Yang, Yosuke Wakutani, William Meadows, Rodylyn Rose Ferry, Liang Dong, Gian Gaetano Tartaglia, Giorgio Favrin, Wen Lang LinDennis 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-Hyslop

Research output: Contribution to journalArticle

236 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)678-690
Number of pages13
JournalNeuron
Volume88
Issue number4
DOIs
StatePublished - Nov 18 2015

Fingerprint

Hydrogels
Ribonucleoproteins
Phase Transition
Mutation
Hydrogel
RNA-Binding Protein FUS
Cytoplasmic Granules
RNA-Binding Proteins
Presynaptic Terminals
Amyloid
RNA
Membranes
Proteins
Therapeutics

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Murakami, T., Qamar, S., Lin, J. Q., Schierle, G. S. K., Rees, E., Miyashita, A., ... St George-Hyslop, P. (2015). ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function. Neuron, 88(4), 678-690. https://doi.org/10.1016/j.neuron.2015.10.030

ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function. / Murakami, Tetsuro; Qamar, Seema; Lin, Julie Qiaojin; Schierle, Gabriele S Kaminski; Rees, Eric; Miyashita, Akinori; Costa, Ana R.; Dodd, Roger B.; Chan, Fiona T S; Michel, Claire H.; Kronenberg-Versteeg, Deborah; Li, Yi; Yang, Seung Pil; Wakutani, Yosuke; Meadows, William; Ferry, Rodylyn Rose; Dong, Liang; Tartaglia, Gian Gaetano; Favrin, Giorgio; Lin, Wen Lang; Dickson, Dennis W; Zhen, Mei; Ron, David; Schmitt-Ulms, Gerold; Fraser, Paul E.; Shneider, Neil A.; Holt, Christine; Vendruscolo, Michele; Kaminski, Clemens F.; St George-Hyslop, Peter.

In: Neuron, Vol. 88, No. 4, 18.11.2015, p. 678-690.

Research output: Contribution to journalArticle

Murakami, T, Qamar, S, Lin, JQ, Schierle, GSK, Rees, E, Miyashita, A, Costa, AR, Dodd, RB, Chan, FTS, 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 2015, 'ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function', Neuron, vol. 88, no. 4, pp. 678-690. https://doi.org/10.1016/j.neuron.2015.10.030
Murakami, Tetsuro ; Qamar, Seema ; Lin, Julie Qiaojin ; Schierle, Gabriele S Kaminski ; Rees, Eric ; Miyashita, Akinori ; Costa, Ana R. ; Dodd, Roger B. ; Chan, Fiona T S ; Michel, Claire H. ; Kronenberg-Versteeg, Deborah ; Li, Yi ; Yang, Seung Pil ; Wakutani, Yosuke ; Meadows, William ; Ferry, Rodylyn Rose ; Dong, Liang ; Tartaglia, Gian Gaetano ; Favrin, Giorgio ; Lin, Wen Lang ; Dickson, Dennis W ; Zhen, Mei ; Ron, David ; Schmitt-Ulms, Gerold ; Fraser, Paul E. ; Shneider, Neil A. ; Holt, Christine ; Vendruscolo, Michele ; Kaminski, Clemens F. ; St George-Hyslop, Peter. / ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function. In: Neuron. 2015 ; Vol. 88, No. 4. pp. 678-690.
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AU - Lin, Julie Qiaojin

AU - Schierle, Gabriele S Kaminski

AU - Rees, Eric

AU - Miyashita, Akinori

AU - Costa, Ana R.

AU - Dodd, Roger B.

AU - Chan, Fiona T S

AU - Michel, Claire H.

AU - Kronenberg-Versteeg, Deborah

AU - Li, Yi

AU - Yang, Seung Pil

AU - Wakutani, Yosuke

AU - Meadows, William

AU - Ferry, Rodylyn Rose

AU - Dong, Liang

AU - Tartaglia, Gian Gaetano

AU - Favrin, Giorgio

AU - Lin, Wen Lang

AU - Dickson, Dennis W

AU - Zhen, Mei

AU - Ron, David

AU - Schmitt-Ulms, Gerold

AU - Fraser, Paul E.

AU - Shneider, Neil A.

AU - Holt, Christine

AU - Vendruscolo, Michele

AU - Kaminski, Clemens F.

AU - St George-Hyslop, Peter

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