Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics.

TitlePhase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics.
Publication TypeJournal Article
Year of Publication2017
AuthorsBoeynaems, S., E. Bogaert, D. Kovacs, A. Konijnenberg, E. Timmerman, A. Volkov, M. Guharoy, M. De Decker, T. Jaspers, V. H. Ryan, A. M. Janke, P. Baatsen, T. Vercruysse, R-M. Kolaitis, D. Daelemans, P. J Taylor, N. Kedersha, P. Anderson, F. Impens, F. Sobott, J. Schymkowitz, F. Rousseau, N. L. Fawzi, W. Robberecht, P. Van Damme, P. Tompa, and L. Van Den Bosch
JournalMol Cell
Date Published2017 Mar 16
KeywordsAmyotrophic Lateral Sclerosis, Arginine, C9orf72 Protein, Carrier Proteins, Cytoplasmic Granules, Dipeptides, DNA Helicases, Eukaryotic Initiation Factor-2, HeLa Cells, Humans, Intrinsically Disordered Proteins, Lipid Droplets, Phosphorylation, Poly-ADP-Ribose Binding Proteins, Protein Domains, Proteins, RNA, RNA Helicases, RNA Recognition Motif Proteins, Time Factors, Transfection

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.

Alternate JournalMol. Cell
PubMed ID28306503
PubMed Central IDPMC5364369
Grant ListT32 MH020068 / MH / NIMH NIH HHS / United States
R01 GM111700 / GM / NIGMS NIH HHS / United States
P20 GM104937 / GM / NIGMS NIH HHS / United States
R35 NS097974 / NS / NINDS NIH HHS / United States
R01 GM118530 / GM / NIGMS NIH HHS / United States
647458 / / European Research Council / International
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