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Phase separation of C9orf72 dipeptide repeats perturbs stress granule dynamics

(2017) MOLECULAR CELL. 65(6). p.1044-1055
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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 eIF2 alpha 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
RNA-BINDING PROTEINS, PRION-LIKE DOMAINS, C-TERMINAL DOMAIN, LIQUID DROPLETS, NUCLEOCYTOPLASMIC TRANSPORT, NEURODEGENERATIVE DISEASE, HEXANUCLEOTIDE REPEAT, GGGGCC REPEAT, IN-VITRO, ALS

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Chicago
Boeynaems, Steven, Elke Bogaert, Denes Kovacs, Albert Konijnenberg, Evy Timmerman, Alex Volkov, Mainak Guharoy, et al. 2017. “Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics.” Molecular Cell 65 (6): 1044–1055.
APA
Boeynaems, S., Bogaert, E., Kovacs, D., Konijnenberg, A., Timmerman, E., Volkov, A., Guharoy, M., et al. (2017). Phase separation of C9orf72 dipeptide repeats perturbs stress granule dynamics. MOLECULAR CELL, 65(6), 1044–1055.
Vancouver
1.
Boeynaems S, Bogaert E, Kovacs D, Konijnenberg A, Timmerman E, Volkov A, et al. Phase separation of C9orf72 dipeptide repeats perturbs stress granule dynamics. MOLECULAR CELL. 2017;65(6):1044–55.
MLA
Boeynaems, Steven, Elke Bogaert, Denes Kovacs, et al. “Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics.” MOLECULAR CELL 65.6 (2017): 1044–1055. Print.
@article{8550044,
  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 eIF2 alpha 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.},
  author       = {Boeynaems, Steven and Bogaert, Elke and Kovacs, Denes and Konijnenberg, Albert and Timmerman, Evy and Volkov, Alex and Guharoy, Mainak and De Decker, Mathias and Jaspers, Tom and Ryan, Veronica H and Janke, Abigail M and Baatsen, Pieter and Vercruysse, Thomas and Kolaitis, Regina-Maria and Daelemans, Dirk and Taylor, J Paul and Kedersha, Nancy and Anderson, Paul and Impens, Francis and Sobott, Frank and Schymkowitz, Joost and Rousseau, Frederic and Fawzi, Nicolas L and Robberecht, Wim and Van Damme, Philip and Tompa, Peter and Van Den Bosch, Ludo},
  issn         = {1097-2765},
  journal      = {MOLECULAR CELL},
  keyword      = {RNA-BINDING PROTEINS,PRION-LIKE DOMAINS,C-TERMINAL DOMAIN,LIQUID DROPLETS,NUCLEOCYTOPLASMIC TRANSPORT,NEURODEGENERATIVE DISEASE,HEXANUCLEOTIDE REPEAT,GGGGCC REPEAT,IN-VITRO,ALS},
  language     = {eng},
  number       = {6},
  pages        = {1044--1055},
  title        = {Phase separation of C9orf72 dipeptide repeats perturbs stress granule dynamics},
  url          = {http://dx.doi.org/10.1016/j.molcel.2017.02.013},
  volume       = {65},
  year         = {2017},
}

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