期刊
MOLECULAR CELL
卷 65, 期 6, 页码 1044-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2017.02.013
关键词
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资金
- KU Leuven
- VIB
- European Research Council (ERC) [340429]
- Research Foundation Flanders (FWO) [G.0983.14N]
- Interuniversity Attraction Poles Programme [P7/16]
- Belgian Science Policy Office
- Association Belge contre les Maladies Neuro-Musculaires (ABMM)
- ALS Liga (Belgium)
- Opening the Future Fund
- E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders
- Hart voor ALS Fund, KU Leuven
- Alzheimer Research Foundation (SAO-FRA) [S14007]
- Flemish Government
- European Union Joint Programme-Neurodegenerative Disease Research (JPND) project RiMod-FTD
- European Research Council under European Union ERC [647458]
- VIB, KU Leuven
- FWO
- Agency for Innovation by Science and Technology (IWT, SBO) [60839]
- NIGMS of the NIH [R01GM118530]
- Institutional Development Award (IDeA) [P20GM104937]
- NIH [T32 MH020068]
- IWT
- Odysseus grant [G0F8616N]
- Odysseus grant from FWO [G.0029.12]
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.
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