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Publication

Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics.

Molecular cell | 2017

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.

Pubmed ID: 28306503 RIS Download

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Associated grants

Agency: NIMH NIH HHS, United States
Id: T32 MH020068
Agency: NIGMS NIH HHS, United States
Id: R01 GM111700
Agency: NIGMS NIH HHS, United States
Id: P20 GM104937
Agency: NINDS NIH HHS, United States
Id: R35 NS097974
Agency: NIGMS NIH HHS, United States
Id: R01 GM118530
Agency: European Research Council, International
Id: 647458

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