Molecular Dissection of FUS Points at Synergistic Effect of Low-Complexity Domains in Toxicity

Elke Bogaert, Steven Boeynaems, Masato Kato, Lin Guo, Thomas Caulfield, Jolien Steyaert, Wendy Scheveneels, Nathalie Wilmans, Wanda Haeck, Nicole Hersmus, Joost Schymkowitz, Frederic Rousseau, James Shorter, Patrick Callaerts, Wim Robberecht, Philip Van Damme, Ludo Van Den Bosch

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

RNA-binding protein aggregation is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). To gain better insight into the molecular interactions underlying this process, we investigated FUS, which is mutated and aggregated in both ALS and FTLD. We generated a Drosophila model of FUS toxicity and identified a previously unrecognized synergistic effect between the N-terminal prion-like domain and the C-terminal arginine-rich domain to mediate toxicity. Although the prion-like domain is generally considered to mediate aggregation of FUS, we find that arginine residues in the C-terminal low-complexity domain are also required for maturation of FUS in cellular stress granules. These data highlight an important role for arginine-rich domains in the pathology of RNA-binding proteins. Protein aggregation is a hallmark of ALS. Bogaert et al. describe the molecular interactions between disordered regions of the FUS protein driving its liquid phase behavior, maturation, and neurotoxicity. These findings highlight the physicochemical interactions driving FUS phase separation and give us insights into its misregulation in disease.

Original languageEnglish (US)
Pages (from-to)529-537.e4
JournalCell Reports
Volume24
Issue number3
DOIs
StatePublished - Jul 17 2018

Fingerprint

Dissection
Amyotrophic Lateral Sclerosis
Frontotemporal Lobar Degeneration
Toxicity
Arginine
RNA-Binding Proteins
Agglomeration
Molecular interactions
Prions
RNA-Binding Protein FUS
Pathology
Phase behavior
Phase separation
Neurodegenerative Diseases
Drosophila
Liquids
Proteins

Keywords

  • amyotrophic lateral sclerosis
  • frontotemporal lobar degeneration
  • FUS
  • intrinsically disordered protein
  • LLPS
  • low-complexity domain
  • phase transition
  • prion-like domain
  • protein aggregation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Bogaert, E., Boeynaems, S., Kato, M., Guo, L., Caulfield, T., Steyaert, J., ... Van Den Bosch, L. (2018). Molecular Dissection of FUS Points at Synergistic Effect of Low-Complexity Domains in Toxicity. Cell Reports, 24(3), 529-537.e4. https://doi.org/10.1016/j.celrep.2018.06.070

Molecular Dissection of FUS Points at Synergistic Effect of Low-Complexity Domains in Toxicity. / Bogaert, Elke; Boeynaems, Steven; Kato, Masato; Guo, Lin; Caulfield, Thomas; Steyaert, Jolien; Scheveneels, Wendy; Wilmans, Nathalie; Haeck, Wanda; Hersmus, Nicole; Schymkowitz, Joost; Rousseau, Frederic; Shorter, James; Callaerts, Patrick; Robberecht, Wim; Van Damme, Philip; Van Den Bosch, Ludo.

In: Cell Reports, Vol. 24, No. 3, 17.07.2018, p. 529-537.e4.

Research output: Contribution to journalArticle

Bogaert, E, Boeynaems, S, Kato, M, Guo, L, Caulfield, T, Steyaert, J, Scheveneels, W, Wilmans, N, Haeck, W, Hersmus, N, Schymkowitz, J, Rousseau, F, Shorter, J, Callaerts, P, Robberecht, W, Van Damme, P & Van Den Bosch, L 2018, 'Molecular Dissection of FUS Points at Synergistic Effect of Low-Complexity Domains in Toxicity', Cell Reports, vol. 24, no. 3, pp. 529-537.e4. https://doi.org/10.1016/j.celrep.2018.06.070
Bogaert, Elke ; Boeynaems, Steven ; Kato, Masato ; Guo, Lin ; Caulfield, Thomas ; Steyaert, Jolien ; Scheveneels, Wendy ; Wilmans, Nathalie ; Haeck, Wanda ; Hersmus, Nicole ; Schymkowitz, Joost ; Rousseau, Frederic ; Shorter, James ; Callaerts, Patrick ; Robberecht, Wim ; Van Damme, Philip ; Van Den Bosch, Ludo. / Molecular Dissection of FUS Points at Synergistic Effect of Low-Complexity Domains in Toxicity. In: Cell Reports. 2018 ; Vol. 24, No. 3. pp. 529-537.e4.
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