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Mol Cell. 2017 Mar 16;65(6):1044-1055.e5. doi: 10.1016/j.molcel.2017.02.013.

Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics.

Author information

1
Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), Department of Neurosciences, KU Leuven - University of Leuven, 3000 Leuven, Belgium; Laboratory of Neurobiology, VIB, Center for Brain and Disease Research, 3000 Leuven, Belgium.
2
Center for Structural Biology (CSB), VIB, Vrije Universiteit Brussel (VUB), 1050 Brussels, Belgium.
3
Biomolecular and Analytical Mass Spectrometry Group, Department of Chemistry, University of Antwerp, 2020 Antwerp, Belgium.
4
VIB-UGent Center for Medical Biotechnology, 9000 Gent, Belgium; VIB Proteomics Core, 9000 Gent, Belgium; Department of Biochemistry, Ghent University, 9000 Gent, Belgium.
5
Neuroscience Graduate Program, Brown University, Providence, RI 02912, USA.
6
Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA.
7
VIB, Bioimaging Core Facility, 3000 Leuven, Belgium.
8
Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven, 3000 Leuven, Belgium.
9
Howard Hughes Medical Institute, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
10
Division of Rheumatology, Immunology, and Allergy, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
11
Biomolecular and Analytical Mass Spectrometry Group, Department of Chemistry, University of Antwerp, 2020 Antwerp, Belgium; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK; School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.
12
Switch Laboratory, Center for Brain and Disease Research, VIB, 3000 Leuven, Belgium; Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.
13
Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), Department of Neurosciences, KU Leuven - University of Leuven, 3000 Leuven, Belgium; Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium.
14
Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), Department of Neurosciences, KU Leuven - University of Leuven, 3000 Leuven, Belgium; Laboratory of Neurobiology, VIB, Center for Brain and Disease Research, 3000 Leuven, Belgium; Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium.
15
Center for Structural Biology (CSB), VIB, Vrije Universiteit Brussel (VUB), 1050 Brussels, Belgium; Institute of Enzymology, Research Centre for Natural Sciences of the Hungarian Academy of Sciences, 1117 Budapest, Hungary. Electronic address: ptompa@vub.ac.be.
16
Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), Department of Neurosciences, KU Leuven - University of Leuven, 3000 Leuven, Belgium; Laboratory of Neurobiology, VIB, Center for Brain and Disease Research, 3000 Leuven, Belgium. Electronic address: ludo.vandenbosch@vib-kuleuven.be.

Abstract

Liquid-liquid phase separation (LLPS) of RNA-binding proteins plays an important role in the formation of multiple membrane-less organelles involved in RNA metabolism, including stress granules. Defects in stress granule homeostasis constitute a cornerstone of ALS/FTLD pathogenesis. Polar residues (tyrosine and glutamine) have been previously demonstrated to be critical for phase separation of ALS-linked stress granule proteins. We now identify an active role for arginine-rich domains in these phase separations. Moreover, arginine-rich dipeptide repeats (DPRs) derived from C9orf72 hexanucleotide repeat expansions similarly undergo LLPS and induce phase separation of a large set of proteins involved in RNA and stress granule metabolism. Expression of arginine-rich DPRs in cells induced spontaneous stress granule assembly that required both eIF2α phosphorylation and G3BP. Together with recent reports showing that DPRs affect nucleocytoplasmic transport, our results point to an important role for arginine-rich DPRs in the pathogenesis of C9orf72 ALS/FTLD.

KEYWORDS:

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

PMID:
28306503
PMCID:
PMC5364369
DOI:
10.1016/j.molcel.2017.02.013
[Indexed for MEDLINE]
Free PMC Article

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