title: A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation.
abstract: Many proteins contain disordered regions of low-sequence complexity, which cause aging-associated diseases because they are prone to aggregate. Here, we study FUS, a prion-like protein containing intrinsically disordered domains associated with the neurodegenerative disease ALS. We show that, in cells, FUS forms liquid compartments at sites of DNA damage and in the cytoplasm upon stress. We confirm this by reconstituting liquid FUS compartments in vitro. Using an in vitro "aging" experiment, we demonstrate that liquid droplets of FUS protein convert with time from a liquid to an aggregated state, and this conversion is accelerated by patient-derived mutations. We conclude that the physiological role of FUS requires forming dynamic liquid-like compartments. We propose that liquid-like compartments carry the trade-off between functionality and risk of aggregation and that aberrant phase transitions within liquid-like compartments lie at the heart of ALS and, presumably, other age-related diseases.
authors: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors: Avinash
authors: A
authors: Patel
authors: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors: Hyun O
authors: HO
authors: Lee
authors: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany; Max Planck Institute for the Physics of Complex Systems, 01187 Dresden, Germany.
authors: Louise
authors: L
authors: Jawerth
authors: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors: Shovamayee
authors: S
authors: Maharana
authors: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors: Marcus
authors: M
authors: Jahnel
authors: Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors: Marco Y
authors: MY
authors: Hein
authors: Institute of Molecular Biology, Bulgarian Academy of Sciences, 21, G. Bontchev Str., Sofia 1113, Bulgaria.
authors: Stoyno
authors: S
authors: Stoynov
authors: Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors: Julia
authors: J
authors: Mahamid
authors: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors: Shambaditya
authors: S
authors: Saha
authors: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors: Titus M
authors: TM
authors: Franzmann
authors: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors: Andrej
authors: A
authors: Pozniakovski
authors: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors: Ina
authors: I
authors: Poser
authors: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors: Nicola
authors: N
authors: Maghelli
authors: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors: Loic A
authors: LA
authors: Royer
authors: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors: Martin
authors: M
authors: Weigert
authors: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors: Eugene W
authors: EW
authors: Myers
authors: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors: Stephan
authors: S
authors: Grill
authors: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors: David
authors: D
authors: Drechsel
authors: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany. Electronic address: hyman@mpi-cbg.de.
authors: Anthony A
authors: AA
authors: Hyman
authors: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany. Electronic address: alberti@mpi-cbg.de.
authors: Simon
authors: S
authors: Alberti
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002467:Cell Nucleus / Q000737:chemistry; D003593:Cytoplasm / Q000737:chemistry; D006801:Humans; D009154:Mutation; D011328:Prions / Q000737:chemistry; D066329:Protein Aggregates; D017434:Protein Structure, Tertiary; D034702:RNA-Binding Protein FUS / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: C000599550:FUS protein, human; D011328:Prions; D066329:Protein Aggregates; D034702:RNA-Binding Protein FUS