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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.
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“Liquid‐to‐gel transitions were previously suggested for condensates of the RNA binding proteins FUS (Patel et al, 2015) and hnRNPA1 (Molliex et al, 2015), and for Tau in the presence of molecular crowding by us and others (Wegmann et al, 2018; Kanaan et al, 2020).”
From Molecular crowding and RNA synergize to promote phase separation, microtubule interaction, and seeding of Tau condensates (2022) · cites this paper as Patel et al, 2015
In the citing paper
“Biomolecular condensates of different neurodegenerative disease‐associated proteins have been shown to progressively percolate and subsequently transit into aggregates (Molliex et al, 2015; Patel et al, 2015; Ray et al, 2020).”
From Molecular crowding and RNA synergize to promote phase separation, microtubule interaction, and seeding of Tau condensates (2022) · cites this paper as Patel et al, 2015
In the citing paper
“Recently, it was shown that before FUS converts into insoluble deposits, it undergoes liquid–liquid phase separation (LLPS)28–30.”
From Liquid–liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau (2017) · cites this paper as [29]
In the citing paper
“In contrast to K18, domains of proteins, which were previously shown to undergo LLPS (e.g., FUS), are glutamine/asparagine-rich and undergo liquid demixing only at low temperature (below 20 °C)28–30.”
From Liquid–liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau (2017) · cites this paper as [29]
In the citing paper
“In addition, disease mutations in FUS leading to amyotrophic lateral sclerosis accelerate the transition from the liquid demixed state to an aberrant aggregated form28, 29.”
From Liquid–liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau (2017) · cites this paper as [29]
Citations
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Coactivator condensation at super-enhancers links phase separation and gene control
Sabari, B. R., Dall’Agnese, A., Boija, A., Klein, I. A., Coffey, E. L., Shrinivas, K., Abraham, B. J., Hannett, N. M., Zamudio, A. V., Manteiga, J. C., et al. (2018) · Science · doi:10.1126/science.aar3958 · Cited by 2,595
The proteostasis network and its decline in ageing
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G3BP1 is a tunable switch that triggers phase separation to assemble stress granules
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Tau protein liquid–liquid phase separation can initiate tau aggregation
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Self-citationValence and patterning of aromatic residues determine the phase behavior of prion-like domains
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Metadata
- Authors
- Patel, A., Lee, H. O., Jawerth, L., Maharana, S., Jahnel, M., Hein, M. Y., Stoynov, S., Mahamid, J., Saha, S., Franzmann, T. M., Pozniakovski, A., Poser, I., Maghelli, N., Royer, L. A., Weigert, M., Myers, E. W., Grill, S., Drechsel, D., Hyman, A. A., & Alberti, S.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 162
- Issue
- 5
- Pages
- 1066-1077
- ISSN
- 0092-8674
- Cited by
- 3,282
- References
- 6
- Language
- en
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